Polymers containing diester units

ABSTRACT

The present invention relates to biodegradable polymers containing diester units of formula (I) 
     
         --CO--O--C(R.sup.1 R.sup.2)--O--CO-- 
    
     where R 1  and R 2  each represents a hydrogen atom or a carbon-attached monovalent organic group, or R 1  and R 2  together form a carbon-attached divalent organic group.

This invention concerns polymers containing optionally substitutedmethylene diester groupings. Such groupings are capable of beingbiodegradable since they are labile to common esterase enzymes althoughin many instances the polymer may remain at least partly intact.

Biodegradable polymers have long been used in the medical field, forexample to provide biodegradable implant materials and delayed releasedrug delivery systems. They are now of wider interest in overcoming theproblem of pollution by long-lived insert packaging materials, householdarticles, detergents and the like.

There is also a need for polymers which, when they wholly or partiallybreak down by chemical or biological means, give reliably non-toxicproducts.

In general, biodegradation commonly involves enzymic hydrolysis ofparticular chemical bonds in the polymer, notably ester, urethane oramide groups which are otherwise stable in the absence of enzymes. Thus,for packaging materials, aliphatic polyesters such as polycaprolactone,polyethylene adipate and polyglycolic acid are candidate materialsalthough polyethylene terephthalate, which is very widely used intextiles and fibres, is resistant to biodegradation.

In the medical field, resorbable polymers are of interest for suturesand in wound closure, resorbable implants in the treatment ofosteomyelitis and other bone lesions, tissue stapling and meshtamponades, anastomosis as well as drug delivery systems anddiagnostics. In these fields, polylactic acid, polyglycolic acid, poly(L-lactide-co-glycolide), polydioxanone, poly (glycolide-co-trimethylenecarbonate), poly (ethylene carbonate), poly (iminocarbonates),polyhydroxybutyrate, poly (amino acids), poly (ester-amides), poly(orthoesters) and poly (anhydrides) have all been proposed (T. H.Barrows, Clinical Materials 1 (1986), pp. 233-257) as well as naturalproducts such as polysaccharides. U.S. Pat. No. 4,180,646, inparticular, describes novel poly (orthoesters) for use in a very widerange of products.

However, the polymers hitherto proposed for either medical or moregeneral use have each had one or more disadvantages and there is ademand for alternative polymers, in particular polymers containingreadily biodegradable groupings. The present invention is based in theconcept that diester units of the formula (I)

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--                       (I)

(where R¹ and R² are as defined below) are particularly rapidly degradedby common esterase enzymes but are stable in the absence of enzymes.

A number of polymers containing such units have been described in theprior art. Thus, for example, U.S. Pat. No. 2,341,334 describes thecopolymerisation of monomers such as methylidene or ethylidenedimethacrylate with ethylenic monomers such as vinyl acetate, methylmethacrylate or styrene. The resulting copolymers are said to exhibithigher softening points than unmodified homopolymers of the ethylenicmonomer and to be useful in the preparation of cast articles. DD-A-95108and DE-A-1104700 similarly describe the copolymerisation of variousalkylidene diacrylate esters with acrylic monomers to yield copolymerswith modified physical properties. A number of alkylidene dicrotonatesare disclosed in U.S. Pat. No. 2,839,572 as monomers which may behomopolymerised or copolymerised with materials such as vinyl chloride,to yield resins useful as protective coatings. Kimura H. in J. OsakaUniv. Dent. Sch., 20 (1980), pp. 43-49 describes the use of propylidynetrimethacrylate as a crosslinking agent in coating dentalpolymethylmethacrylate in order to improve its abrasion resistance.Homopolymers of ethylidene, allylidene and benzylidene dimethacrylateare described in FR-A-2119697 and by Arbuzova A. et al. in Zh. Obshch.Khim. 26 (1956), pp. 1275-1277, and typically comprise hard, glassymaterials.

EP-A-0052946 discloses the use of certain polyacrylates to stabilisepolyhydroxybutyric acid. The only polyacrylate having more than oneacryloyloxy group attached to a single carbon atom is pentaerithritylmonohydroxypentaacrylate, which by virtue of its numerous ethylenicallyunsaturated sites would be expected to form a complex mixture ofaddition polymers with polyhydroxybutyric acid.

U.S. Pat. No. 3,293,220 describes use of aldehyde dicarboxylates tostabilise polyoxymethylene polymers by acylating the terminal hydroxylgroups. There is no suggestion of cross-linking or incorporation of thealdehyde dicarboxylate residues into the polymer chains.

In such prior art, the diester grouping of formula (I) is introducedinto the polymers by polymerisation of an alkylidene diacrylate ordimethacrylate monomer by a free radical mechanism whereby the olefinicbonds polymerise to form polyolefinic chains to which the diester groupsare attached in side chains or crosslinking groups. The diester groupingis always of the form in which, referring to formula (I), both carbonylgroups are joined directly to carbon, that is neither of the estergroups is other than a simple carboxylic ester group.

None of this prior art suggests that the diester groupings disclosedtherein may be biodegradable; indeed, the introduction of crosslinkinggroups of the type represented by formula (I) above is generally seen asconveying enhanced rigidity and/or stability.

According to the present invention we have found it possible to preparenovel diester polymers containing linkages of formula (I) above whichexhibit high stability in the absence of enzymes, which linkages aredegradable by esterases both in the natural environment, e.g. bybacterial attack, and in the human or animal body, to form non-toxicproducts, even where structural elements of the polymer, e.g. polymerbackbone chains, retain their integrity.

In contrast to the diester-containing polyolefinic polymers described inthe prior art, which typically are rigidly crosslinked, polymer of theinvention may exhibit the property, even when polyolefinic, of beingwater-swellable. This can convey a number of advantages, for exampleassisting the ingress of water-borne enzymes into the polymer structure,thereby facilitating biodegraditive attack. Water-swellable polymers mayalso be treated with aqueous or hydrophilic solutions of, for example,biologically active or diagnostic agents, whereby such agents areincorporated into the polymer. In further embodiments of the inventionsuch agents may also be physically incorporated into the diesterpolymers during polymerisation or may be covalently bonded either toappropriate monomers which are subsequently polymerised or to preformedpolymers.

Thus according to one aspect of the invention we provide polymerscontaining diester units of the formula (I) where R¹ and R² eachrepresents a hydrogen atom or a carbon-attached monovalent organic groupor R¹ and R² together form a carbon-attached divalent organic group,with the proviso that where such units are attached at both ends tocarbon atoms and the polymers are polyolefinic, then the polymers arebiodegradable and/or are water-swellable and/or are associated with abiologically active or diagnostic agent.

In general, biodegradable polymers are preferred. Polyolefinic polymershave the potential disadvantage of possessing carbon-carbon backbonechains which are not readily degraded although this may not bedisadvantageous where the polymers are water-swellable and/or containbiological or diagnostic agents and/or where the polymer backbone chainsare water-soluble or dispersible, e.g. after degradation of diestercrosslinking groups.

The term `diester` as used herein refers to the presence of two--CO--O-- groups in the units of formula (I). These may be attached notonly to carbon-attached organic groups, as in simple carboxylic esters,but to --O-- atoms as in carbonate esters.

Thus polymers of the invention may be represented as containing units ofthe formula (II)

    --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m ](II)

where R¹ and R² are as defined above and m and n, which may be the sameor different, are each 0 or 1.

In general, the polymers of the invention will contain units of theformula (III)

    --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3 ](III)

where R¹, R², m and n have the above meanings and R^(]) is acarbon-attached divalent organic grouping.

The polymers of the invention may advantageously be of relatively lowmolecular weight, since this may aid both biodegradation and dispersalof the degradation products. Accordingly the term "polymer" as usedherein in relation to the invention should be understood to include lowmolecular weight materials such as oligomers.

Polymers according to the invention may comprise a plurality of units offormula (III) having different meanings for m, n, R¹, R² and R³ forexample as in block or graft copolymers. The diester linkages may occurat intervals throughout the polymer, e.g. as crosslinking groups orbetween copolymer sections, in which case R³ will represent a polymericgrouping. Alternatively the linkages may be present throughoutsubstantially the whole of the polymer, in which case R³ will preferablybe a low-molecular grouping.

Particularly interesting units (III) are those in which n is 0 and m is0 or 1, i.e. dicarboxylate units of the formula (IV)

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--R.sup.3 ]              (IV)

or carboxylate-carbonate units of the formula (V)

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--O--R.sup.3 ]           (V)

The latter are of particular interest and have not been describedpreviously in polymers of any kind.

R¹ and R² may, for example, each be hydrogen or a carbon-attachedhydrocarbyl or heterocyclic group, for example having 1-20 carbon atoms,e.g. an aliphatic group such as an alkyl or alkenyl group (preferablyhaving up to 10 carbon atoms), a cycloalkyl group (preferably having upto 10 carbon atoms), an araliphatic group such as an aralkyl group(preferably having up to 20 carbon atoms), an aryl group (preferablyhaving up to 20 carbon atoms) or a heterocyclic group having up to 20carbon atoms and one or more heteroatoms selected from O,S and N. Such ahydrocarbyl or heterocyclic grouping may carry one or more functionalgroups such as halogen atoms or groups of the formulae --NR⁴ R⁵,--CONR⁴R⁵,--OR⁶, --SR⁶ and --COOR⁷, where R⁴ and R⁵, which may be the same ordifferent are hydrogen atoms, acyl groups or hydrocarbyl groups asdefined for R¹ and R² ; R⁶ is a hydrogen atom or an acyl group or agroup as defined for R¹ or R² and R⁷ is a hydrogen atom or a group asdefined for R¹ or R². Where R¹ and R² represent a divalent grouping thismay be an alkylidene, alkenylidene, alkylene or alkenylene group(preferably having up to 10 carbon atoms), which may carry one or morefunctional groups as defined above.

As indicated above, the diester groupings of formula (I) may beseparated by a wide range of groupings. Where it is desired that thepolymer should break down into relatively short sections to aidbiodegradation, the group R³ which separates the diester units offormula (II) may, for example, be an alkylene or alkenylene group (e.g.containing up to 20, more preferably up to 10 carbon atoms), acycloalkylene group (preferably having up to 10 carbon atoms), anarylene group (containing one or more aromatic rings and preferablyhaving up to 20 carbon atoms), an aralkylene group (preferably having upto 20 carbon atoms and which may be bonded via the aryl and/or alkylmoieties--such aralkyl groups include, for example, two aryl groupsjoined by an alkylene chain) or a heterocyclic group having one or morehetero-atoms selected from O, S and N (preferably having up to 20 carbonatoms). The group R³ may carry functional groups, e.g. as set out abovefor R¹ and R² and/or substituents such as oxo groups; the carbon chainsof R³ groups may be interrupted by heteroatoms such as O, N or S, e.g.in conjunction with oxo substituents to form linkages such as ester,thioester or amide groups.

Where the group R³ comprises a polymeric grouping, this may, forexample, be a poly(amino acid) such as a polypeptide, or a polyamide,poly(hydroxy acid), polyester, polycarbonate, polysaccharide,polyoxyethylene, polyvinyl alcohol or polyvinyl ether/alcohol grouping.

The wide range of possible groups R¹, R² and R³ enables thehydrophobicity or hydrophilicity of the polymer to be adjusted to anyrequired use. Thus, the polymers may be water-soluble orwater-insoluble.

Aliphatic groups present as, for example, R¹ and R² may be straight orbranched, saturated or unsaturated and include, for example, alkyl andalkenyl groups, e.g. methyl, ethyl, isopropyl, butyl or allyl groups.Araliphatic groups include (monocarbocyclic aryl)-alkyl groups, forexample benzyl groups. Aryl groups include mono- or bi-cyclic arylgroups, for example phenyl, tolyl or naphthyl groups. Heterocyclicgroups include 5- or 6-membered heterocyclic groups preferably havingone heteroatom, for example furyl, thienyl or pyridyl groups. Halogenatom substituents may, for example, be chlorine, bromine or iodine.

Polymers according to the invention carrying functional groups or doublebonds may serve as substrates for subsequent covalent attachment ofbiologically active materials such as drugs (e.g. antibacterial orantineoplastic agents), steroids and other hormones, and agrochemicalssuch as weedkillers and pesticides, or of materials such as diagnosticagents (e.g. X-ray and MRI contrast agents) and may be sold in this formto users who will attach their own active material. However, theinvention also extends to polymers containing units of formula (III)wherein R¹, R² and/or R³ carry covalently-attached biologically activeor diagnostic materials. Suitable active materials are exhaustivelylisted in U.S. Pat. No. 4,180,646 referred to above, the contents ofwhich are incorporated herein by reference.

In general, any biodegradation of the diester groupings of formula (I)will take place by enzymic hydrolytic cleavage of the bonds linking thegroup --O--C(R¹ R²)--O-- to the adjacent carbonyl groups, generallyyielding an aldehyde or ketone of the formula R¹ --CO--R². Theintervening sections, typified by --CO--(O)_(m) --R³ --(O)_(n) --CO-- inthe polymers of formula (III) will form different products according towhether m or n is 0 or 1. Where m or n is 0, hydrolytic cleavage willgenerally yield a carboxyl group; where m or n is 1, a hypotheticalcarbonic acid group --R³ --O--COOH is formed which generally eliminatescarbon dioxide to form a grouping --R³ --OH. This can be of use whereliberation of carbon dioxide is physiologically or functionallydesirable.

Polymers used for medical purposes must form nontoxic, physiologicallyacceptable degradation products. Thus, the groups R¹, R² and R³ shouldbe such that degradation products such as the compound R¹ --CO--R² andthe products HOOC--R³ --COOH, HO--R³ --COOH or HO--R³ --OH arephysiologically acceptable and readily dispersible, preferably beingwater-soluble. Carbon dioxide liberated by cleavage of the carbonategroupings will normally be physiologically acceptable.

As indicated above, the units of formula (III) may be different withinthe same polymer, i.e. the polymers may be copolymers such as block orgraft copolymers. The polymers may be copolymers formed withnon-biodegradable monomers; the non-biodegradable sections remainingafter enzymic or other cleavage are preferably of acceptable size toensure their water-solubility or water-dispersibility and thus permitready dispersal or removal: it is possible to consider suchnon-biodegradable sections as part of the groupings R³ in formula (III)which, in effect, link together the biodegradable groupings of formula(II).

The polymers may be linear, branched or crosslinked. Branched andcrosslinked polymers will in general make use of functional groups ordouble bonds in the corresponding R¹, R² or R³ groups of their monomers.The resulting crosslinked or branched polymers will thus contain someunits of formula (III) wherein R¹, R² and/or R³ are substituted with thecrosslinking or branched chains. It is particularly useful for the groupR³ to be derived from an amino acid which will in general be non-toxicand soluble on cleavage. Dicarboxylic acids such as glutamic or asparticacid can be used to make polymers containing --CO--R³ --CO-- units whilehydroxy-amino acids such as serine or threonine can be used to makepolymers containing --CO--O--R³ --CO-- units. The α-amino group of theamino acid will comprise a functional amino substituent on R³ or thepoint of attachment of a branching or crosslinking chain. Crosslinkingagents can for example include di- or polyfunctional molecules such asdiols (for linking carboxyl groups) or diacids or diisocyanates (forlinking hydroxyl or amino groups).

In general, where the carbon atoms linking the groups R³ to thegroupings of formula (II) are chiral, the chirality is preferably thatfound in natural products since the degrading enzymes will generally actmore efficiently on such structures. The L-configuration of amino-acidunits is thus preferred. However D-isomers are also cleavable and it maybe more convenient in many instances to use isomer mixtures rather thanmaterial of only the optimal chirality. It is possible to make use ofthe different rates of enzymic hydrolysis of D- and L-isomers to producea controlled rate of degradation.

It has been generally observed that in crosslinked biodegradablepolymers the crosslinking sections are often degraded first, thusexposing the rest of the network to enzymic hydrolysis. It isparticularly useful, therefore, to have groupings of formula (II) in thecrosslinking chains of a polymer. One possibility is thus to convert awater-soluble long chain natural or synthetic non-biodegradable orslowly biodegradable substance, e.g. a protein such as gelatin oralbumin, a polysaccharide or oligosaccharide, or a short chainpolyacrylamide, into a water-insoluble form by crosslinking usingcrosslinking units containing groupings of formula (II). This mayminimise the cost of the final product by reducing the amount of therelatively expensive biodegradable units of formula (II).

Block copolymers may, for example, have the structure

    --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m--R.sup.3 ].sub.q.sup.A [(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3 ].sub.r.sup.B

where the respective values of R¹, R², R³ m and n are such that therepeating units in blocks A and B are different and q and r areintegers, e.g. 10-20. One or more further blocks may be attached tothose shown above.

The polymers of the invention may be prepared in any convenient way, forexample by one of the methods set out below.

(A) Synthesis of a homopolymer comprising units of formula (III) inwhich n is 0 and m is 0 or 1 by condensation polymerisation of acompound of the formula (VI)

    X--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3 --COOR.sup.8(VI)

where R⁸ is a metal ion such as silver, sodium, potassium or lithium, Xis a leaving group, e.g. chlorine, bromine, iodine or ahydrocarbylsulphonyloxy group such as a mesyloxy or tosyloxy group, m is0 or 1 and R¹,R² and R³ have the above meanings.

The compound of formula (VI) may be prepared by reaction of thecorresponding acid in which R⁸ is hydrogen with an appropriate base,whereupon polymerisation will normally take place in situ.

The acid of formula (VI) in which R⁸ is hydrogen and m is 1 may beprepared by condensation of a compound of formula (VII)

    HO--R.sup.3 --COOH                                         (VII)

with a compound of formula (VIII)

    X--C(R.sup.1 R.sup.2)--O--CO--X.sup.1                      (VIII)

where X¹ is a chlorine bromine or iodine atom and R¹, R², R³ and X havethe above meanings. The reaction is preferably effected in the presenceof a weakly nucleophilic base such as pyridine in a solvent for thereactants such as a halogenated hydrocarbon, e.g. chloroform.

The acid of formula (VI) in which R⁸ is hydrogen and m is 0 may beprepared by reaction of a compound of the formula (IX)

    Phenyl-S--C(R.sup.1 R.sup.2)--O--CO--R.sup.3 --COOH        (IX)

(where R¹,R² and R³ have the above meanings) with a halogenating agentsuch as sulphonyl chloride, conveniently in a halogenated hydrocarbonsolvent such as dichloromethane.

The compound of formula (IX) may be made by reaction of a compound offormula (X) ##STR1## with a compound of the formula (XI)

    Phenyl-S--C(R.sup.1 R.sup.2)--X.sup.1                      (XI)

where R¹, R², R³ and X¹ have the above meanings, conveniently in a polarsolvent such as dimethylformamide.

(B) Synthesis of a homopolymer comprising units of formula (III) inwhich m and n are 0 by condensation of a compound of the formula (XII)

    R.sup.8 O--CO--R.sup.3 --CO--OR.sup.8                      (XII)

where R⁸ is a metal ion as defined above and R³ has the above meaning,with a compound of the formula (XIII)

    X--C(R.sup.1 R.sup.2)--X                                   (XIII)

where the groups X, which may be the same or different have the meaningsgiven above, preferably chlorine, bromine or iodine, and R¹ and R² havethe above meanings. The compound of formula (XII) may be prepared fromthe corresponding acid in which R⁸ is hydrogen by reaction with anappropriate base, whereupon polymerisation will normally take place insitu.

The acid of formula (XII) wherein R⁸ is hydrogen and m is 0 may beprepared by deprotecting the corresponding compound of formula (XII) inwhich R⁸ is a carboxyl protecting group, e.g. a readily hydrolysed groupsuch as t-butyl. This may be removed by addition of base, e.g. sodium orpotassium hydroxide to yield compound (XII) directly and hence initiatepolymerisation.

(C) Condensation polymerisation of a compound of the formula HR⁹--R^(3A) --(O)_(n) --CO--O--C(R¹ R²)--O--CO--(O)_(m) --R^(3B) --COOHwhere R¹, R², m and n have the above meanings, R^(3A) and R^(3B) areeach groups as defined for R³ and R⁹ is O or NR⁴ (where R⁴ is a hydrogenatom, an acyl group or a hydrocarbyl group as defined for R¹), to give apolymer with repeating units (XIV)

    --R.sup.9 --R.sup.3A --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3B --CO--              (XIV)

Such a polymer may be formed under the conditions conventional forpolyester or polyamide condensations. It will be appreciated that such arepeating unit (XIV) corresponds to a unit of formula (III) in which R³comprises the grouping --R^(3B) --CO--R⁹ --R^(3A) --.

The starting material may be formed by deprotection of the correspondingcompound having a protected carboxyl and/or --R⁹ H group. The latter maybe synthesised by reacting a compound of the formula (XV)

    HO--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3B --COOR.sup.A(XV)

where R¹, R², R^(3B) and m have the above meanings and R^(A) is aprotecting group, with a compound (XVI)

    R.sup.B R.sup.9 --R.sup.3A --(O).sub.n --CO--Cl            (XVI)

where R^(3A), R⁹ and n have the above meanings and R^(B) is a protectinggroup.

The compound (XV) may be prepared by coupling a compound (XVII)

    R.sup.C O--C(R.sup.1 R.sup.2)--OH                          (XVII)

with a compound (XVIII)

    Cl--CO--(O).sub.m --R.sup.3B --COOR.sup.A                  (XVIII)

where R¹, R², R^(3B), R^(A) and m have the above meanings and R^(C) is aprotecting group which is subsequently removed. The compound of formula(XVII) may be made by reaction of a compound R¹ --CO--R² as definedabove with an alcohol R^(C) OH to form a hemiacetal.

(D) Reaction of a compound R¹ --CO--R², optionally together with acompound HO--R³ --OH, with phosgene in the presence of a base such aspyridine to give a product containing units of the formula (XIX).

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--O--R.sup.3 --O]        (XIX)

Some units will be formed of the formula (XX)

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--O--C(R.sup.1 R.sup.2)--O--(XX)

but it should be noted that the definition of R³ given above includes--C(R¹ R²)--, so that the latter units are within the definition offormula (III). Homopolymers containing such units may also be producedby reaction of the compound R¹ --CO--R² with phosgene in the presence ofa base such as pyridine.

(E) Reaction of a compound of the formula (XXI)

    R.sup.10 --R.sup.3A --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3B --R.sup.11          (XXI)

(where R¹, R², R^(3A), R^(3B), m and n have the above meanings and R¹⁰and R¹¹, which may be the same or different, optionally together withthe groups R^(3A) and R^(3B) to which they are attached, are reactivefunctional groupings) with a difunctional compound of the formula (XXII)

    R.sup.12 --R.sup.3C --R.sup.13                             (XXII)

where R^(3C) is a group as defined for R³ and R¹² and R¹³, which may bethe same or different, are reactive functional groups capable ofreacting with R¹⁰ and R¹¹ whereby a polymer according to the inventionis formed, or R¹² and R¹³ separately or together form a polymerisablegroup or groups capable of interaction with R¹⁰ and R¹¹, for example soas to generate a polymerised version of compound (XXII) containingcrosslinking groups derived from compound (XXI).

The functional groupings R¹⁰ and R¹¹ may, for example, be leaving groupssuch as halogen atoms e.g. chlorine or bromine (as in haloalkyl groups;α-halomethyl ester groups; α-halomethyl keto groups; or halocarbonyl orhalosulphonyl groups such as alkanoyl or sulphonyl halides) orsulphonate ester groups, e.g. alkyl sulphonate esters such as mesyloxygroups and aromatic sulphonate esters such as tosyloxy groups; oractivated carboxyl groups, e.g. symmetrical or mixed anhydrides; oractivated hydroxyl groups; or with R^(3A) and/or R^(3B) form activatedalkenes, e.g. α,β-unsaturated ketones and esters; epoxy groups; oraldehyde and ketone groups and acetals and ketals thereof.

The compound (XXII) may, for example, be a relatively short divalentmonomer or preformed polymer whereby a copolymer is formed, or apolyvalent natural or synthetic polymeric material such as a protein orcarbohydrate which will be crosslinked by the reagent of formula (XXI).In such cases the groups R¹² and R¹³ may be nucleophilic groups such ashydroxyl or amino, which commonly occur in natural polymers such ascarbohydrates and proteins and which will react with the groupings R¹⁰and R¹¹ listed above. It will be appreciated that R¹⁰ and R¹¹ mayequally be groups such as hydroxyl or amino, while R¹² and R¹³ aregroups reacting with these as listed for R¹⁰ and R¹¹.

Polymerisable compounds of formula (XXII) include those in which R¹² andR¹³ form an optionally substituted ethylenically unsaturated group, e.g.a vinyl group. Examples of such compounds thus include vinyl monomerssuch as vinyl acetate and styrene and acrylic and methacrylic monomerssuch as acrylic acid, methacrylic acid, methyl acrylate, methylmethacrylate, acrylamide, methacrylamide, acrylonitrile,methacrylonitrile, hydroxyethyl methacrylate and hydroxypropylmethacrylate. Compounds of this type may be copolymerised with compoundsof formula (XXI) in which R¹⁰ and R¹¹ comprise ethylenically unsaturatedgroups, e.g. under conditions appropriate for free radicalpolymerisation, to yield appropriately crosslinked polymers.

Reagents of formula (XXI) are new and constitute a further feature ofthe invention.

Polymers in accordance with the invention may, for example, be producedin a single solution phase whereby a mass of insoluble polymericmaterial is formed; after solvent removal this material may be shapedfor the required end use e.g. as sheets, fibres, particles or articlessuch as surgical implants. Un-crosslinked polymers according to theinvention will in general be thermoplastic and so may be shaped (e.g. bycalendering, drawing or moulding) at elevated temperature to form aparticular desired product. Films of polymers according to the inventionmay, for example, be made by solvent casting.

The polymers may also be produced by emulsion polymerisation to giveparticles of the polymeric material; a solution of the monomer(s) in awater-immiscible organic solvent may be dispersed in an aqueous phaseand polymerisation then initiated. Thus, for example, in reactions (A)and (B) above, where formation of a salt initiates polymerisation, theacid (VI) in reaction (A) or the protected acid (XII) in reaction (B)may be dissolved in an organic solvent such as a halogenated hydrocarbonand emulsified, for example by sonication. Addition of a base such assodium hydroxide to the aqueous phase, optionally with a phase transferagent, then initiates polymerisation. Heating may be desirable topromote polymerisation. Methods of emulsion polymerisation to produceparticles, especially monodisperse particles, are described inEP-A-0003905, EP-A-0091453, EP-A-0010986 and EP-A-0106873.

Polymers according to the invention, e.g. containing units of formula(III) as hereinbefore defined, find utility in, for example, surgicalimplants such as sutures, soft tissue prostheses, sponges, films (e.g.artificial skin) or wound dressings (e.g. hydrogel sheets), flexiblesheet materials and articles such as containers formed therefrom. Suchpolymers are advantageously biodegradable. Biodegradable polymers alsofind use in, for example, the manufacture of biodegradable delayedrelease formulations for drugs or agricultural chemicals, andhorticultural aids such as water-retaining "mulch" sheeting and plantcontainers. Such usages and the polymers shaped for use therein comprisefurther features of the invention. For use as prostheses, the shapedpolymers may advantageously carry heparin, at least on the surfacethereof.

Where a polymer of the invention is to be used as a biodegradabledelayed release agent, the active material may be contained within ashell of the biodegradable polymer, e.g. in a capsule or inmicrospheres, or it may be physically incorporated during polymerisationso that it is uniformly distributed within the polymer and is releasedduring biodegradation. Alternatively, the active material may compriseall or part of any of the groups R¹, R² or R³ and thus be released bythe enzymatic cleavage. Typical drugs for incorporation in delayedrelease formulations include steroids, contraceptives, antibacterials,narcotics-antagonists and anti-tumour drugs.

The polymers of the invention, when of appropriately short chain length,may be used as plasticisers for other polymers. Where the polymers ofthe invention are biodegradable, degradation of the plasticiser thuseither breaks up the integrity of the material or opens it up to attackby enzymes.

Biodegradable polymer particles according to the invention can alsoadvantageously be used for diagnostic purposes. Thus an X-ray contrastagent, which will normally be a poly-iodo aromatic compound, may formall or part of the group R³ or --C(R¹ R²)-- so that it is liberated andsafely eliminated from the body on biodegradation. Such particles may beused for visualisation of the liver and spleen since they are trapped inthe reticuloendothelial systems of those organs. The X-ray contrastagent may also be simply held physically in the polymers by beingincorporated during polymerisation.

Polymer particles according to the invention may also containparamagnetic, superparamagnetic or ferromagnetic substances which are ofuse in magnetic resonance imaging (MRI) diagnostics. Thus, submicronparticles of iron or a magnetic iron oxide can be physicallyincorporated into the polymers during polymerisation to provideferromagnetic or superparamagnetic particles. Paramagnetic MRI contrastagents principally comprise paramagnetic metal ions, such as gadoliniumions, held by a chelating agent which prevents their release (and thussubstantially eliminates their toxicity). Such chelating agents withcomplexed metal ions may be physically held in the polymers by beingpresent during polymerisation or the groups R¹, R² and R³ may comprisesuitable chelating groups. In general many such chelating agents arepoly-amino polycarboxylic acids such as diethylene triamine pentaaceticacid (R. B. Lauffer, Chem. Rev. 87 (1987), pp. 901-927).

Polymer particles of the invention may also contain ultrasound contrastagents such as heavy materials, e.g. barium sulphate or iodinatedcompounds such as the X-ray contrast agents referred to above, toprovide ultrasound contrast media.

The following Examples are given by way of illustration only.

EXAMPLE 1 Poly(1,6-dioxa-2,5-dioxoheptylene)

To a mixture of di-sodium succinate (1.0 equiv.) in an appropriateamount of dimethylformamide is added diiodomethane (1.0 equiv.). Thereaction mixture is stirred at ambient temperature until the main amountof the reagents are consumed, dialysed to remove low molecular weightmaterial, and evaporated to give the title double ester polymer havingrepeating units of formula ##STR2## i.e. units (II) in which R¹ =R² =H,R³ =--CH₂ --CH₂ -- and m=n=0.

EXAMPLE 2 Poly(2,6-dimethyl-4,7-dioxo-1,3,5-trioxaheptylene)

To a mixture of 1-chloroethyl chloroformate (1.1 equiv.) and(S)-2-hydroxypropionic acid (1.0 equiv.) in an appropriate amount ofdimethylformamide is added dropwise pyridine (1.0 equiv.) at atemperature below 12° C. The reaction mixture is stirred at ambienttemperature until the majority of the reagents are consumed, dialysed toremove low molecular weight material, and evaporated to give the titlecarbonate ester polymer having repeating units of formula ##STR3## i.e.units (II) in which R¹ =H, R² =CH₃, R³ =CH(CH₃), m=1 and n=0.

EXAMPLE 3

a) Mono-glycoyloxymethyl succinate

To a mixture of sodium glycolate (1.0 equiv.) in an approriate amount ofdimethylformamide, is dropwise added benzyl chlorometyl succinate (1.0equiv.--prepared in accordance with Benneche, Strande and Wiggen, ActaChem. Scand. 43 (1988), pp. 74-77) in dimethylformamide at ambienttemperature. The reaction mixture is stirred at 50° C. until themajority of the reactants are consumed, concentrated, and extracted intochloroform/sodium carbonate solution. The organic phase is dried andevaporated to give the benzyl ester of the title product. Catalytichydrogenation in conventional manner removes the benzyl group, and thetitle compound is thus obtained, having the formula

    HO--CO--CH.sub.2 --CH.sub.2 --CO--O--CH.sub.2 --O--CO--CH.sub.2 --OH

b) Poly(5,7,10-trioxa-1,4,8-trioxodecylene)

A mixture of mono-glycoyloxymethyl succinate and a catalytic amount ofp-toluenesulphonic acid in dry toluene is refluxed under a nitrogenatmosphere until water ceases to form. The solvent is removed at 200° C.and a pressure of 0.1 mm Hg, to give the title polymer having repeatingunits of the formula ##STR4## i.e. units (II) in which R¹ =R² =H, R³=--CH₂ --O--CO--CH₂ --CH₂ -- and m=n=0.

EXAMPLE 4

a) Methylene dimethacrylate

A solution of potassium hydroxide (1.00M, 40.00 ml) is added tomethacrylic acid (3.44 g, 40.00 mmol) at 0° C. and the solution freezedried for 16 hours. Dry dimethylformamide (230 ml) is added and thesuspension heated to 60° C. under a dry nitrogen atmosphere.Diiodomethane (1.61 ml, 20.00 mmol) is added in two portions during 10min. and the reaction mixture left for 4 days at 60° C. The solvent isremoved under reduced pressure (0.05 mm Hg), before diethyl ether (140ml), saturated aqueous sodium hydrogen carbonate (50 ml) and water (50ml) are added. The aqueous layer is extracted with diethyl ether (6×60ml) and the combined ether extracts washed with water (4×50 ml), dried(MgSO₄), and evaporated to give 2.63 g (72%) of the title compound. ¹ HNMR (60 MHz, CDCl₃): δ 1.97 (2× CH₃, m), 5.63 (2×H--C═, m), 5.88 (CH₂,s), 6.18 (2×H--C═, m). IR (film, cm⁻¹): 2987 (w), 2962 (w), 2930 (w),1732 (str), 1638 (w), 1454 (w), 1315 (w), 1295 (w), 1158 (w), 1100(str), 1012 (m), 989 (m).

b) Methylene diacrylate

A solution of potassium hydroxide (1.00M, 40.00 ml) is added to acrylicacid (2.88 g, 40.00 mmol) at 0° C. and the solution freeze dried for 16hours. Dry dimethylformamide (200 ml) is added and the suspension heatedto 60° C. under a dry nitrogen atmosphere. Diiodomethane (1.61 ml, 20.00mmol) is added in two portions during 10 min. and the reaction mixtureleft for 4 days at 60° C. The solvent is removed under reduced pressure(0.05 mm Hg), before diethyl ether (140 ml), saturated aqueous sodiumhydrogen carbonate (50 ml) and water (50 ml) are added. The aqueouslayer is extracted with diethyl ether (6×60 ml) and the combined etherextracts washed with water (4×50 ml), dried (MgSO₄), and evaporated togive 1.06 g (34%) of the title compound. ¹ H NMR (60 MHz, CDCl₃): δ5.81-6.61 (2×CH₂ =CH--, m), 5.84 (CH₂, s).

c) Chloromethyl (2-methacryloyloxy)ethyl carbonate

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution ofchloromethyl chloroformate (0.89 ml, 11.00 mmol) and 2-hydroxyethylmethacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 0° C.under a dry nitrogen atmosphere. After 21 hours at 20° C. the reactionmixture is washed with hydrochloric acid (1.00M, 10 ml), saturatedaqueous sodium hydrogen carbonate (10 ml) and water (10 ml). The organicphase is dried (MgSO₄) and the solvent evaporated under reduced pressure(10 mm Hg) to give 1.97 g (88%) of the title compound. ¹ H NMR (60 MHz,CDCl₃): δ 1.88 (CH₃, d, J=2 Hz), 4.35 (O--CH₂ --CH₂ --O, m), 5.47(H--C═, m), 5.63 (CH₂ --Cl, s), 6.00 (H--C═, m).

d) (2-Methacryloyloxy)ethyl methacryloyloxymethyl carbonate

A solution of potassium hydroxide (1.00M, 5.00 ml) is added tomethacrylic acid (0.43 g, 5.00 mmol) at 0° C. and the solution freezedried during 16 hours. Dry dimethylformamide (50 ml) is added and to theresulting suspension is added chloromethyl (2-methacryloyloxy)ethylcarbonate (1.11 g, 5.00 mmol). 18-Crown-6 (0.066 g, 0.25 mmol) is addedas a catalyst and the reaction left under a dry nitrogen atmosphere.After 24 hours at 20° C. and 6 days at 4° C. the solvent is removedunder reduced pressure (0.05 mm Hg) and diethyl ether (30 ml) and water(20 ml) added. The aqueous layer is extracted with diethyl ether (3×20ml) and the combined ether extracts washed with water (20 ml), dried(MgSO₄) and evaporated to give 1.26 g (93%) of the title compound. ¹ HNMR (60 MHz, CDCl₃): δ 1.97 (2×CH₃, m), 4.38 (O--CH₂ --CH₂ --O, m), 5.53(2×H--C═, m), 5.77 (CH₂, s), 6.07 (2×H--C═, m).

e) Ethylene di(chloromethyl carbonate)

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution ofchloromethyl chloroformate (1.32 ml, 14.83 mmol) and ethylene glycol(0.28 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with goodstirring under a dry N₂ atmosphere. After 15 min. at 7° C. and 6 hoursat 20° C. the reaction mixture is transferred to a separating funnelwith the aid of dichloromethane (10 ml). The reaction mixture is washedwith hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogencarbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO₄)and the solvent evaporated under reduced pressure to give 1.12 g (90%)of the title product. ¹ H NMR (300 MHz, CDCl₃): δ 4.48 (s, O--CH₂ CH₂--O), 5.75 (s, 2×Cl--CH₂ --O). ¹³ C NMR (75 MHz, CDCl₃): δ 65.8 (O--CH₂CH₂ --O), 72.2 (2×Cl--CH₂ --O), 153.0 (2×C═O).

f) Bis(2-chloromethoxycarbonyloxyethyl)ether

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution ofchloromethyl chloroformate (1.32 ml, 14.83 mmol) and diethylene glycol(0.47 ml, 5.00 mmol) in dichloromethane (10 ml) at 7° C. with goodstirring under a dry N₂ atmosphere. After 10 min. at 7° C. and 6 hoursat 20° C. the reaction mixture is transferred to a separating funnelwith the aid of dichloromethane (10 ml). The reaction mixture is washedwith hydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogencarbonate (10 ml) and water (10 ml). The organic phase is dried (MgSO₄)and the solvent evaporated under reduced pressure (10 mm Hg) to give1.26 g (86%) title product. ¹ H NMR (300 MHz, CDCl₃): δ 3.72 (m, 2×CH₂--O), 4.34 (m, 2×CH₂ --O--C═O), 5.71 (s, 2×Cl--CH₂ --O). ¹³ C NMR (75MHz, CDCl₃): δ 67.6 (2×CH₂ --O), 68.5 (2×CH₂ --O--C═O), 72.1 (2×Cl--CH₂--O), 153.2 (2×C═O).

g) 1-Chloroethyl 2-methacryloyloxyethyl carbonate

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 2-hydroxyethylmethacrylate (1.22 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C.under a dry N₂ atmosphere. After 15 min. at 3° C. and 17 hours at 20° C.the reaction mixture is transferred to a separating funnel with the aidof dichloromethane (10 ml). The reaction mixture is washed withhydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogencarbonate (10 ml) and water (2×10 ml). The organic phase is dried(MgSO₄) and the solvent evaporated under reduced pressure to give 1.76 g(74%) of the title product. ¹ H NMR (60 MHz, CDCl₃): δ 1.85 (3 H, d, J=6Hz, CH₃ --CH), 1.96 (3 H,d, J= 2 Hz, CH₃ --C═), 5.55 (1 H, m, CH═), 6.10(1 H, m, CH═), 6.38 (1 H, k, J=6 Hz, CH--CH₃).

h) Chloromethyl 4-acryloyloxybutyl carbonate

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution ofchloromethyl chloroformate (0.98 ml, 11.00 mmol) and 4-hydroxybutylacrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. undera dry N₂ atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. thereaction mixture is transferred to a separating funnel with the aid ofdichloromethane (10 ml). The reaction mixture is washed withhydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogencarbonate (10 ml) and water (2×10 ml). The organic phase is dried(MgSO₄) and the solvent evaporated under reduced pressure to give 1.76 g(74%) of the title product. ¹ H NMR (60 MHz, CDCl₃): δ 1.82 (4 H, m, CH₂--CH₂), 4.27 (4 H, m, 2×CH₂ --O), 5.77 (2 H, s, Cl--CH₂ --O), 5.8-6.7 (3H, m, CH═CH₂).

i) 1-Chloroethyl 4-acryloyloxybutyl carbonate

Pyridine (0.89 ml, 11.00 mmol) is added dropwise to a solution of1-chloroethyl chloroformate (1.20 ml, 11.00 mmol) and 4-hydroxybutylacrylate (1.38 ml, 10.00 mmol) in dichloromethane (12 ml) at 3° C. undera dry N₂ atmosphere. After 15 min. at 3° C. and 17 hours at 20° C. thereaction mixture is transferred to a separating funnel with the aid ofdichloromethane (10 ml). The reaction mixture is washed withhydrochloric acid (1.00M, 10 ml), saturated aqueous sodium hydrogencarbonate (10 ml) and water (2×10 ml). The organic phase is dried(MgSO₄) and the solvent evaporated under reduced pressure to give 2.26 g(90%) of the title product. ¹ H NMR (60 MHz, CDCl₃): δ 1.80 (4 H, m, CH₂--CH₂), 1.86 (3 H, d, J=5 Hz, CH₃), 4.24 (4 H, m, 2×CH₂ --O), 5.7-6.6 (4H, m, CH═CH₂ and CH).

j) 1 -Methacryloyloxyethyl 2-methacryloyloxyethyl carbonate

1-Chloroethyl 2-methacryloyloxyethyl carbonate (1.183 g, 5.00 mmol) isadded to a suspension of freeze dried potassium methacrylate (0.683 g,5.50 mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50ml) under a dry N₂ atmosphere. After 5 days at 20° C. the solvent isremoved under reduced pressure and the residue dissolved by addingdichloromethane (60 ml) and water (30 ml). After separating the phasesthe aqueous layer is extracted with dichloromethane (3×30 ml) and thecombined organic phase washed with saturated aqueous sodium hydrogencarbonate (50 ml). The organic phase is dried (MgSO₄) and the solventremoved under reduced pressure to give 1.10 g (77%) of the titleproduct. ¹ H NMR (60 MHz, CDCl₃): δ 1.63 (3 H, d, J=5 Hz, CH₃ --CH),1.98 (6 H, s, 2×CH₃), 4.42 (4 H, s, O--CH₂ --CH₂ --O), 5.62 (2 H, m,CH═), 6.15 (2 H, m, CH═), 6.84 (1 H, k, J=5 Hz, CH--CH₃).

k) Acryloyloxymethyl 4-acryloyloxybutyl carbonate

Chloromethyl 4-acryloyloxybutyl carbonate (1.183 g, 5.00 mmol) is addedto a suspension of freeze dried potassium acrylate (0.606 g, 5.50mmol)and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under adry N₂ atmosphere. After 5 days at 20° C. the solvent is removed underreduced pressure and the residue dissolved by adding dichloromethane (60ml) and water (30 ml). After separating the phases the aqueous layer isextracted with dichloromethane (3×30 ml) and the combined organic phasewashed with saturated aqueous sodium hydrogen carbonate (50 ml). Theorganic phase is dried (MgSO₄) and the solvent removed under reducedpressure to give 1.24 g (91%) of the title product. ¹ H NMR (60 MHz,CDCl₃): δ 1.82 (4 H, m, CH₂ --CH₂), 4.23 (4 H, m, 2×CH₂ --O), 5.88 (2 H,s, O--CH₂ --O), 5.7-6.8 (6 H, 2×CH═CH₂).

l) 1-Acryloyloxyethyl 4-acryloyloxybutyl carbonate

1-Chloroethyl 4-acryloyloxybutyl carbonate (1.253 g, 5.00 mmol) is addedto a suspension of freeze dried potassium acrylate (0.606 g, 5.50 mmol)and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under adry N₂ atmosphere. After 5 days at 20° C. the solvent is removed underreduced pressure and the residue dissolved by adding dichloromethane (60ml) and water (30 ml). After separating the phases the aqueous layer isextracted with dichloromethane (3×30 ml) and the combined organic phasewashed with saturated aqueous sodium hydrogen carbonate (50 ml). Theorganic phase is dried (MgSO₄) and the solvent removed under reducedpressure to give 1.28 g (89%) of the title product. ¹ H NMR (60 MHz,CDCl₃): δ 1.58 (3 H, d, J=5 Hz, CH₃ --CH), 1.80 (4 H, m, CH₂ --CH₂),4.24 (4 H, m, 2 ×CH₂ --O), 5.7-6.7 (6 H, m, 2×CH═CH₂), 6.87 (1 H, k, J=5Hz, CH--CH₃).

m) Methylene di(p-vinylbenzoate)

Diiodomethane (0.20 ml, 2.50 mmol) is added to a solution of freezedried potassium p-vinylbenzoate (0.931 g, 5.00 mmol), 18-crown-6 (0.040g, 0.25 mmol) and hydroquinone (0.011 g, 0.10 mmol) in dimethylformamide(35 ml) under a dry N₂ atmosphere and the reaction mixture left for 2.5days at 60° C. The solvent is removed under reduced pressure and theresidue dissolved by adding diethyl ether (20 ml), saturated aqueoussodium hydrogen carbonate (5 ml) and water (10 ml). After separating thephases the aqueous layer is extracted with diethyl ether (6×10 ml) andthe combined organic phase washed with water (5×10 ml). The organicphase is dried (MgSO₄) and the solvent removed under reduced pressure togive 0.64 g (83%) of the title product. ¹ H NMR (300 MHz, CDCl₃): δ 5.39(2 H, d, J=10 Hz, 2 ×CH═), 5.86 (2 H, d, J=17.6 Hz, 2×CH═), 6.24 (2 H,s, O--CH2--O), 6.73 (2 H, dd, J=11.0, 17.6, 2×CH═), 7.45 (4 H, 2×d,J=6.8 Hz, Ar), 8.04 (2 H, d, J=6.6 Hz, Ar), 8.05 (2 H, d, J=6.6 Hz, Ar).¹³ C NMR (75 MHz, CDCl₃): δ 79.8 (O--CH₂ --O), 116.8 (2×CH═), 126.0,130.2 (C₂,C₂ ',C₃, C₃ '), 127.8, 142.5 (C₁,C₁ ',C₄,C₄ '), 135.7 (2×CH═),164.9 (2×C═O).

n) Methylene di(p-bromobenzoate)

Diiodomethane (0.60 ml, 7.50 mmol) is added to a solution of freezedried potassium p-bromobenzoate (3.587 g, 15.00 mmol) and 18-crown-6(0.198 g, 0.75 mmol) in dimethylformamide (100 ml) under a dry N₂atmosphere and the reaction mixture left for 4 days at 60° C. Thesolvent is removed under reduced pressure and the residue dissolved byadding dichloromethane (60 ml) and water (30 ml). After separating thephases the aqueous layer is extracted with dichloromethane (3×30 ml) andthe combined organic phase washed with saturated aqueous sodium hydrogencarbonate (50 ml). The organic phase is dried (MgSO₄) and the solventremoved under reduced pressure to give 2.62 g (84%) of the titleproduct. ¹ H NMR (60 MHz, CDCl₃): δ 6.29 (2 H, s, O--CH₂ --O), 7.63 (4H, d, J=9 Hz, Ar), 8.00 (4 H, d, J=9 Hz, Ar).

o) Methylene di(p-hydroxybenzoate)

Diiodomethane (0.40 ml, 5.00 mmol) is added to a solution of freezedried potassium p-hydroxybenzoate (1.762 g, 10.00 mmol) indimethylformamide (60 ml) under a dry N₂ atmosphere and the reactionmixture left for 4 days at 60° C. The solvent is removed under reducedpressure and the residue dissolved by adding dichloromethane (60 ml) andwater (30 ml). After separating the phases the aqueous layer isextracted with dichloromethane (3×30 ml) and the combined organic phasewashed with brine (50 ml). The organic phase is dried (MgSO₄) and thesolvent removed under reduced pressure to give 0.94 g (65%) of the titleproduct. ¹ H NMR (60 MHz, CDCl₃ /CD₃ OD 1:2): δ 4.92 (2 H, s, 2×OH),6.18 (2 H, s, O--CH₂ --O), 6.88 (4 H, d, J=9 Hz, Ar), 7.96 (4 H, d, J=9Hz, Ar).

p) Methylene bis[p-(hydroxymethylethynyl)benzoate]

Bis (triphenylphosphine)palladium dichloride (17.0 mg, 0.02 mmol) andcuprous iodide (2.0 mg, 0.01 mmol) are added to a suspension ofmethylene bis (p-bromobenzoate) prepared as described in Example 4 (n)(0.500 g, 1.21 mmol) and propargyl alcohol (0.16 ml, 2.66 mmol) intriethylamine (10 ml) with good stirring, at 20° C., under a dry N₂atmosphere. After 10 days at 20° C., the triethylamine is removed underreduced pressure, water (20 ml) is added and the mixture is extractedwith dichloromethane (3×15 ml). The dichloromethane phases are washedwith hydrochloric acid (0.5M, 10 ml), dried (MgSO₄) and thedichloromethane removed under reduced pressure to give 0.37 g (85%) ofthe crude product. ¹ H NMR (60 MHz, CDCl₃): δ 3.67 (2 H, s, OH), 4.47 (4H, s, CH₂ --O), 6.18 (2 H, s, O--CH₂ --O), 7.2-7.5 (4 H, Ar), 7.8-8.0 (4H, Ar).

q) Adipic acid bis 1-chloroethyl ester

Anhydrous zinc chloride (10.0 mg, 0.07 mmol) is added to adipoylchloride (2.92 ml, 20.00 mmol) at 20° C., under a dry N₂ atmosphere.Acetaldehyde (2.26 g, 40.00 mmol) is added dropwise to the reactionmixture at -5° C. The reaction temperature is kept between -5° C. and 0°C. and dichloromethane (20 ml) is added. The zinc chloride catalyst isremoved by passing the reaction mixture through a chromatography columncontaining aluminium oxide (Fluka 06290, type 5016 A basic, 20 g) at 5°C. using dichloromethane as the solvent. The solvent is removed underreduced pressure to give 3.64 g (67%) of the crude product. ¹ H NMR (60MHz, CDCl₃): δ 1.5-1.9 (4 H, m, CH₂ --CH₂), 1.77 (6 H, d, J=6 Hz,2×CH₃), 2.1-2.5 (4 H, m, 2×CH₂ --O), 6.49 (2 H, k, J=6 Hz, 2×Cl--CH--O).

EXAMPLE 5

a) Acrylamide polymer powder crosslinked with 5% methylenedimethacrylate

Methylene dimethacrylate prepared as described in Example 4(a) (0.50 g,2.72 mmol) dissolved in dimethylformamide (2 ml) is added to a solutionof acrylamide (10.00 g, 140.70 mmol) and azobisisobutyronitrile (AIBN,0.02 g, 0.86 mmol) in dimethylformamide and the reaction mixture heatedto 60° C. under a dry nitrogen atmosphere. After approximately 50 min.the clear reaction mixture turns into a white suspension. The reactionmixture is kept at 60° C. for a total of 2 hours to complete thereaction. After cooling to 20° C. the reaction mixture is filtered, thesolid washed several times with dimethylformamide and dried under vacuumto yield the title compound as a powder. The product is insoluble inwater in contrast to uncrosslinked polyacrylamide prepared by the samemethod. IR (KBr, cm⁻¹): 3379 (broad, str), 3199 (str), 2932 (w), 1739(m), 1662 (str), 1616 (str), 1451 (m), 1415 (m), 1348 (w), 1320 (w),1102 (w), 976 (w), 610 (broad, m). On subtracting the spectrum ofpolyacrylamide prepared using the same procedure as above from thecrosslinked polyacrylamide, the following peaks originating from theincorporated crosslinker appear: 1740 (str), 1471 (w), 1387 (w), 1152(m), 1084 (str), 963 (str).

b) Acrylamide polymer gel crosslinked with 5% methylene dimethacrylate

AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g,70.34 mmol) and methylene dimethacrylate prepared as described inExample 4(a) (0.250 g, 1.36 mmol) in water/DMSO (90:10,20 ml) at 60° C.under a dry nitrogen atmosphere, with good stirring. After approximately25 min. the reaction mixture turns into a gel and is kept at 60° C. fora total of 2 hours to complete the reaction. The resulting gel is notsoluble in water whereas the corresponding acrylamide homopolymer issoluble.

c) Acrylamide polymer crosslinked with 2.6% methylene dimethacrylate

AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g,70.34 mmol) and methylene dimethacrylate prepared as described inExample 4(a) (0.131 g, 0.709 mmol) in water/DMSO (90:10,20 ml) at 60° C.under a dry nitrogen atmosphere, with good stirring. After approximately25 min. the reaction mixture turns into a gel and is kept at 60° C. fora total of 2 hours to complete the reaction. The resulting gel is notsoluble in water whereas the corresponding acrylamide homopolymer issoluble.

d) Acrylamide polymer crosslinked with 1.3% methylene dimethacrylate

AIBN (0.01 g, 0.43 mmol) is added to a solution of acrylamide (5.00 g,70.34 mmol) and methylene dimethacrylate prepared as described inExample 4(a) (0.065 g, 0.035 mmol) in water/DMSO (90:10, 20 ml) at 60°C. under a dry nitrogen atmosphere, with good stirring. Afterapproximately 25 min. the reaction mixture turns into a gel and is keptat 60° C. for a total of 2 hours to complete the reaction. The resultinggel is not soluble in water whereas the corresponding acrylamidehomopolymer is soluble.

The degree of swelling in water of acrylamide-methylene dimethacrylatecopolymer gels prepared according to this Example is inverselyproportional to the degree of crosslinking as determined by thepercentage of methylene dimethacrylate employed.

EXAMPLE 6

Methyl acrylate polymer crosslinked with 2% methylene diacrylate

AIBN (0.005 g, 0.03 mmol) is added to a solution of methyl acrylate(3.029 g, 35.20 mmol) and methylene diacrylate prepared as described inExample 4(b) (0.110 g, 0.70 mmol) in dimethylformamide (10 ml) at 60° C.under a dry N₂ atmosphere. After approximately 50 min. the clearreaction mixture turns into a gel. The reaction mixture is kept at 60°C. for a total of 2 hours to complete the reaction. The resulting gel isinsoluble in tetrahydrofuran, whereas poly methyl acrylate is soluble.This proves that the gel is crosslinked.

EXAMPLE 7

Acrylic acid polymer crosslinked with 2% methylene diacrylate

AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylic acid (2.534g, 35.20 mmol) and methylene diacrylate prepared as described in Example4(b) (0.110 g, 0.70 mmol) in dimethylformamide (10 ml) at 60° C. under adry N₂ atmosphere. After approximately 60 min. the clear reactionmixture turns into a gel. The reaction mixture is kept at 60° C. for atotal of 2 hours to complete the reaction. The resulting gel isinsoluble in dimethylformamide, whereas poly acrylic acid is soluble.This proves that the gel is crosslinked.

EXAMPLE 8

Acrylamide polymer crosslinked with 0.5% methylene diacrylate

AIBN (0.005 g, 0.03 mmol) dissolved in tetrahydrofuran (2 ml) is addedto a solution of acrylamide (2.500 g, 35.17 mmol) and methylenediacrylate prepared as described in Example 4(b) (0.027 g, 0.18 mmol) intetrahydrofuran (10 ml) at 60° C. under a dry N₂ atmosphere. Afterapproximately 2 hours no visible change is observable in the reactionmixture. AIBN (0.005 g, 0.03 mmol) is therefore added. The polymer thenstarts to precipitate from the reaction mixture and after a total of 5hours the reaction mixture is cooled and filtered. The polymer is washedseveral times with tetrahydrofuran and dried under reduced pressure. Theresulting polymer is insoluble in water, whereas polyacrylamide issoluble. This proves that a crosslinked polymer is formed. TheIR-spectrum of the polymer confirms this structure. Subtracting theIR-spectrum of polyacrylamide prepared by the same procedure as aboveconfirms the incorporation of the crosslinker. The concentration of thecrosslinker (0.5%) is, however, too low to give an accurate "subtractionspectrum" .

EXAMPLE 9

Acrylamide polymer crosslinked with 0.5% 2-methacryloyloxyethylmethacryloyloxymethyl carbonate

AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.500 g,35.20 mmol) and 2-methacryloyloxyethyl methacryloyloxymethyl carbonateprepared as described in Example 4(d) (0.048 g, 0.18 mmol) intetrahydrofuran (10 ml) at 60° C. under a dry N₂ atmosphere. After 2hours no visible change is observed in the reaction mixture. AIBN (0.005g, 0.03 mmol) dissovled in tetrahydrofuran (2 ml) is therefore added.The polymer then starts to precipitate from the reaction mixture andafter a total of 4 hours the reaction mixture is cooled and filtered.The polymer is washed several times with tetrahydrofuran and dried underreduced pressure. IR (KBr, cm⁻¹): 3350 (broad, m), 3198 (m), 2933 (w),1659 (str.), 1617 (m), 1450 (w), 1420 (w). The polymer is soluble inwater giving a viscous solution, suggesting little crosslinking.

EXAMPLE 10

2-Hydroxyethyl methacrylate polymer crosslinked with 0.5%2-methacryloyloxyethyl methacryloyloxymethyl carbonate

AIBN (0.005 g, 0.03 mmol) is added to a solution of 2-hydroxyethylmethacrylate (4.578 g, 35.20 mmol) and 2-methacryloyloxyethylmethacryloyloxymethyl carbonate prepared as described in Example 4(d)(0.0479 g, 0.18 mmol) in tetrahydrofuran (10 ml) at 60° C. under a dryN₂ atmosphere. After one hour tetrahydrofuran (10 ml) is added and thereaction mixture turns into a gel. The reaction mixture is kept at 60°C. for a total of 2 hours to complete the reaction. The resulting gel isinsoluble in dichloromethane, whereas poly 2-hydroxyethyl methacrylateis soluble. This proves that the gel is crosslinked.

EXAMPLE 11

Methyl methacrylate polymer crosslinked with 2% acryloyloxymethyl4-acryloyloxybutyl carbonate

AIBN (0.005 g, 0.03 mmol) is added to a solution of methyl acrylate(3.029 g, 35.20 mmol) and acryloyloxymethyl 4-acryloyloxybutyl carbonateprepared as described in Example 4(k) (0.192 g, 0.70 mmol) indimethylformamide (10 ml) at 60° C. under a dry N₂ atmosphere. After 1hour the clear reaction mixture turns into a gel. The reaction mixtureis kept at 60° C. for a total of 2 hours to complete the reaction. Theresulting gel is insoluble in tetrahydrofuran, whereas poly methylmethacrylate is soluble. This proves that the gel is crosslinked.

EXAMPLE 12

Acrylamide polymer crosslinked with 2% acryloyloxymethyl4-acryloyloxybutyl carbonate

AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.502 g.35.20 mmol) and acryloyloxymethyl 4-acryloyloxybutyl carbonate preparedas described in Example 4(k) (0.202 g, 0.74 mmol) in dimethylformamide(10 ml) at 60° C. under a dry N₂ atmosphere. After approximately 40 min.the reaction mixture turns white and the polymer starts to precipitate.The reaction mixture is cooled and filtered after a total of 2 hours at60° C. The polymer is washed several times with dimethylformamide anddried under reduced pressure. IR (KBr, cm⁻¹): 3387 (broad, m), 3195 (m),2932 (w), 2360 (w), 1661 (str.), 1611 (m), 1451 (w), 1415 (w). Thepolymer product is insoluble in water, whereas polyacrylamide issoluble. This proves that the polymer is crosslinked.

EXAMPLE 13

Acrylamide polymer crosslinked with 2% 1-acryloyloxyethyl4-acryloyloxybutyl carbonate

AIBN (0.005 g, 0.03 mmol) is added to a solution of acrylamide (2.502 g.35.20 mmol) and 1-acryloyloxyethyl 4-acryloyloxybutyl carbonate preparedas described in Example 4(l) (0.202 g, 0.70 mmol) in dimethylformamide(10 ml) at 60° C. under a dry N₂ atmosphere. After approximately 30 min.the polymer starts to precipitate from the reaction mixture. Thereaction mixture is cooled and filtered after a total of 2 hours at 60°C. The polymer is washed several times with dimethylformamide and driedunder reduced pressure. IR (KBr, cm⁻¹): 3390 (broad, m), 3197 (m), 2933(w), 1661 (str.), 1611 (m), 1452 (w), 1415 (w). The polymer product isinsoluble in water, whereas polyacrylamide is soluble. This providesthat the polymer is crosslinked.

EXAMPLE 14

Poly (methylene terephthalate)

A solution of potassium hydroxide (1.00M, 10.00 ml) is added toterephthalic acid (0.83 g, 5.00 mmol) at 0° C. and the solution freezedried during 16 hours. Dry dimethylformamide (50 ml) is added and thesuspension heated to 70° C. under a dry nitrogen atmosphere.Diiodomethane (1.61 ml, 20.00 mmol) and 18-crown-6 (0.066 g, 0.25 mmol)are added and the reaction mixture kept for 3 days at 70° C. and 3 daysat 100° C. The solvent is removed under reduced pressure (0.05 mm Hg),whereafter diethyl ether (30 ml) and water (30 ml) are added. The pH ofthe aqueous suspension is adjusted to 9 with sodium hydroxide (1.00M)before washing with diethyl ether (3×30 ml). The aqueous suspension iscentrifuged, the liquid decanted off and the solid resuspended inabsolute ethyl alcohol. Centrifugation and decantation are repeated andthe solid dried under vacuum to give 0.29 g (32%) of the product as apowder. IR (KBr, cm⁻¹): 3400 (w, broad), 1732 (str), 1600 (w), 1558 (w),1456 (w), 1400 (w), 1288 (m), 1256 (m), 1244 (m), 1158 (w), 1118 (w),1053 (str), 1014 (m), 978 (m), 727 (m). The solubility properties of theproduct indicate that a polymer is formed.

EXAMPLE 15

Polymer from ethylene di(chloromethyl carbonate) and terephthalic acid

Ethylene di(chloromethyl carbonate) prepared as described in Example4(e) (0.489 g, 1.98 mmol) is added to a suspension of freeze drieddi-potassium terephthalate (0.480 g, 1.98 mmol) and 18-crown-6 (0.027 g,0.10 mmol) in dimethylformamide (20 ml). After 2 days at 20° C. thereaction mixture is heated to 60° C. and kept there for 3 weeks. Thesolvent is removed under reduced pressure and the residue dissolved byadding dichloromethane (60 ml) and water (30 ml). After separating thephases the dichloromethane phase is washed with saturated aqueous sodiumhydrogen carbonate (30 ml) and brine (30 ml). The organic phase is dried(MgSO₄) and the solvent removed under reduced pressure to give 0.35 g(53%) of the title product. ¹ H NMR (60 MHz, CDCl₃): δ 4.47 (4 H, s,O--CH₂ CH₂ --O), 6.02 (4 H, s, 2×O--CH.sub. 2 --O), 8.12(4 H, s, Ar).High temperature gel filtration chromatography (GPC) indicates thatfractions of the material have a molecular weight exceeding 20,000 withrespect to poly(ethylene glycol) as standard.

EXAMPLE 16

Polyester from methylene di(p-hydroxybenzoate) and adipoyl chloride

Pyridine (0.560 ml, 6.94 mmol) is added dropwise to a solution ofmethylene di(p-hydroxybenzoate) prepared as described in Example 4(o)(1.00 g, 3.47 mmol) and adipoyl chloride (0.635 g, 3.47 mmol) in drydichloromethane (30 ml) at 20° C. under a dry N₂ atmosphere. After 18hours at 20° C. water (10 ml) is added to the reaction mixture and thephases are separated. The aqueous layer is extracted withdichloromethane (3×10 ml) and the combined organic phases are washedwith water (3×20 ml). The volume of the organic phase is increased to250 ml by adding more dichloromethane. The resulting organic phase isdried (MgSO₄) and the solvent evaporated under reduced pressure (0.1mmHg) to give 0.93 g (67%) product. ¹ H NMR (300 MHz, CDCl₃): δ 1.76 (4H, m, CH₂ --CH₂), 2.59 (4 H, m, 2×CH₂ -- C═O), 6.20 (2 H, s, O--CH₂--O), 7.16 (4 H, At), 8.06 (4 H, Ar). High temperature gel filtrationchromatography (GPC) indicates that fractions of the material have amolecular weight exceeding 20,000 with respect to poly(ethylene glycol)as standard.

EXAMPLE 17

Polymer from bis (2-chloromethoxycarbonyloxyethyl) ether anddi-potassium fumarate

Bis(2-chloromethoxycarbonyloxyethyl) ether prepared as described inExample 4(f) (1.456 g, 5.00 mmol) is added to a suspension ofdi-potassium fumarate (0.961 g, 5.00 mmol) and 18-crown-6 (0.039 g, 0.15mmol) in DMF (50 ml) and the reaction mixture is heated to 60° C., undera dry N₂ atmosphere. After 11 days at 60° C. the solvent is removedunder reduced pressure. Chloroform (40 ml) is added to the residue andthe organic layer washed with water (3×30 ml). The combined waterwashings are extracted with chloroform (3×20 ml). The combined organicphases are concentrated in vacuo to give 1.57 g (94%) of a brown oilproduct. ¹ H NMR (300 MHz, DMSO-d₆, 40° C.): δ 3.78 (4 H, m, 2×CH₂ --O),4.38 (4 H, m, 2×CH₂ --O--C═O), 5.94 (4 H, s, 2×O--CH₂ --O), 6.98 (2 H,s, CH═CH). High temperature gel filtration chromatography (GPC)indicates that fractions of the material have a molecular weightexceeding 20,000 with respect to poly(ethylene glycol) as standard.

EXAMPLE 18

Methylene bis [p-2,3-epoxy-1-propyloxy)benzoate]

Potassium tert.butoxide (1.347 g, 12.00 mmol) is added to a solution ofmethylene di(p-hydroxybenzoate) prepared as described in Example 4(o)(1.728 g, 6.00 mmol) in DMF (75 ml), under a dry N₂ atmosphere.Epichlorohydrin (2.22 g, 24.00 mmol) is added and after 24 hours at 20°C. the solvent is removed under reduced pressure. The residue isdissolved by adding dichloromethane (75 ml) and water (30 ml) andadjusting the pH to neutral using hydrochloric acid (1M). Afterseparating the phases the dichloromethane layer is washed with water(3×30 ml). The organic phase is dried (MgSO₄) and the solvent removedunder reduced pressure to give 1.22 g (51%) product as a colourless oil.¹ H NMR (60 MHz, CDCl₃): δ 2.8 (4 H, m, 2×epoxy-CH₂), 3.3 (2 H, m,2×epoxy-CH), 4.05 (2 H, dd, J=22, 11 Hz, 2×O--CH--H), 4.12 (2 H, dd,J=22, 11 Hz, 2×O--CH--H), 6.14 (2 H, s, O--CH₂ --O), 6.9 (4 H, m, 2×Ar),7.9 (4 H, m, 2×Ar).

EXAMPLE 19

Hexamethylene di(chloromethyl carbonate)

Pyridine (1.77 ml, 22.00 mmol) is added dropwise to a solution ofchloromethyl chloroformate (2.61 ml, 29.70 mmol) and 1,6-hexanediol(1.182 g, 10.00 mmol) in dichloromethane (40 ml) at 7° C. with goodstirring under a dry N₂ atmosphere. After 15 min. at 7° C. and 6 hoursat 20° C. the reaction mixture is transferred to a separating funnelwith the aid of dichloromethane (2×10 ml). The reaction mixture iswashed with hydrochloric acid (1.00M, 20 ml), saturated aqueous sodiumhydrogen carbonate (20 ml) and water (20 ml). Ethyl acetate is added tothe organic phase to get a clear solution. This solution is dried(MgSO₄) and the solvent evaporated under reduced pressure to give 2.76 g(99%) product. ¹ H NMR (300 MHz, CDCl₃): δ 1.2-2.0 [8 H, m, (CH₂)₄ ],4.22 [4 H, t, J=6 Hz, 2×(CH₂ --O)], 5.73 [4 H, s, 2×Cl--CH₂ --O)].

EXAMPLE 20

Polymer from adipic acid bis 1-chloroethyl ester and di-potassiumterephthalate

Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution ofterephthalic acid (0.831 g, 5.00 mmol) in DMF (50 ml) at 20° C., under adry N₂ atmosphere. Adipic acid bis 1-chloroethyl ester prepared asdescribed in Example 4(q) (1.356 g, 5.00 mmol) is added to the resultingsuspension and the reaction mixture heated to 60° C. After 1 hour at 60°C., 18-crown-6 (0.066 g, 0.25 mmol) is added. The solvent is removedunder reduced pressure after 8 days at 60° C. and the residue dissolvedby adding chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodiumhydroxide (1M, 50 ml). After separating the phases the aqueous phase isextracted with chloroform (3×25 ml). The combined organic layers arewashed with water (2×50 ml) and dried (MgSO₄). The solvent is removedunder reduced pressure to give 0.238 g (13%) of crude product.

EXAMPLE 21

Polymer from adipic acid bis 1-chloroethyl ester and di-potassiumfumarate

Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution offumaric acid (0.580 g, 5.00 mmol) in DMF (50 ml) at 20° C., under a dryN₂ atmosphere. Adipic acid bis 1-chloroethyl ester prepared as describedin Example 4(q) (1.356 g, 5.00 mmol) is added to the resultingsuspension and the reaction mixture heated to 60° C. After 1 hour at 60°C., 18-crown-6 (0.066 g, 0.25 mmol) is added. The solvent is removedunder reduced pressure after 8 days at 60° C. and the residue dissolvedby adding chloroform (60 ml), ethyl acetate (30 ml) and aqueous sodiumhydroxide (1M, 50 ml). After separating the phases the aqueous phase isextracted with chloroform (3×25 ml). The combined organic layers arewashed with water (2×50 ml) and dried (MgSO₄). The solvent is removedunder reduced pressure to give 0.276 g (18%) of crude product.

EXAMPLE 22

Poly(methylene adipoate)

Potassium tert.butoxide (1.122 g, 10.00 mmol) is added to a solution ofadipic acid (0.731 g, 5.00 mmol) in DMF (50 ml) at 20° C., under a dryN₂ atmosphere. Adipic acid bis chloromethyl ester (prepared according toRosnati: Bovet. Rend. 1st. super Sanita 15 (1951), 473, 486) (1.215 g,5.00 mmol) is added to the resulting suspension and the reaction mixtureheated to 60° C. After 1 hour at 60° C., 18-crown-6 (0.066 g, 0.25 mmol)is added. The solvent is removed under reduced pressure after 8 days at60° C. and the residue dissolved by adding chloroform (60 ml), ethylacetate (30 ml) and aqueous sodium hydroxide (1M, 50 ml). Afterseparating the phases the aqueous phase is extracted with chloroform(3×25 ml). The combined organic layers are washed with water (2×50 ml)and dried (MgSO₄). The solvent is removed under reduced pressure to give0.618 g (39%) of crude product. ¹ H NMR (60 MHz, CDCl₃): δ 1.67 (4 H, m,broad, CH₂ --CH₂), 2.37 (4 H, m, broad, 2×CH₂ --O), 5.77 (2H, s, O--CH₂--O).

EXAMPLE 23

Polymer from hexamethylene di(chloromethyl carbonate) and di-potassiumterephthalate

Potassium tert.butoxide (0.804 g, 7.16 mmol) is added to a solution ofterephthalic acid (0.595 g, 3.58 mmol) in DMF (40 ml) at 20° C., under adry N₂ atmosphere. Hexamethylene di(chloromethyl carbonate) prepared asdescribed in Example 19 (1.00 g, 3.58 mmol) and 18-crown-6 (0.047 g,0.179 mmol) are added to the resulting suspension and the reactionmixture heated to 60° C. The solvent is removed under reduced pressureafter 6 days at 60° C. The residue is insoluble in dichloromethane andsodium hydroxide (1M), indicating the formation of a polymer.

EXAMPLE 24

Methylene di(3,3,-dimethoxypropionate)

Cesium 3,3-dimethoxypropionate (19.95 g, 75 mmol) is added to dry DMF(11). Diiodomethane (10.04 g, 37.5 mmol) is added to the suspension andthe reaction mixture is stirred for 2 days at 60° C. under a dry N₂atmosphere. DMF is removed under reduced pressure (0.01 mmHg). Diethylether (500 ml) is added to the residue, which is then washed withsaturated aqueous sodium hydrogen carbonate (250 ml). The aqueous layeris extracted with diethyl ether (5×75 ml). The combined ether extractsare washed with water (2×100 ml), dried (MgSO₄) and evaporated to give7.1 g (72%) product. ¹ H NMR (300 MHz, CDCl₃): δ 2.61 (CH₂, d), 3.26(CH₃, s), 4.76 (CH,t), 5.70 (CH₂, s). ¹³ C NMR (300 MHz, CDCl₃): δ 38.52(CH₂), 53.37 (CH₃ O), 79.02 (OCH₂ O), 168.32 (C═O).

EXAMPLE 25

Epoxy resin based on methylene bis[p-2,3-epoxy-1-propyloxy))benzoate]and an aliphatic polyamine

A sample of methylene bis[p-(2,3-epoxy-1-propyloxy)benzoate] prepared asdescribed in Example 18 is blended with an equal weight of a commercialaliphatic polyamine curing agent. This mixture is used as an adhesive toadhere two glass plates together at room temperature. The resin isobserved to have hardened and good bonding is obtained within 24 hoursof mixing.

EXAMPLE 26

Aqueous polymer gel prepared by crosslinking an aqueous solution ofpoly(vinyl-alcohol) with methylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18%solution). To this solution, 0.10 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 isadded, and the solution is well mixed. After 24 hours at roomtemperature the viscosity of the solution is higher than initially, andafter 48 hours at room temperature the solution has formed a relativelystrong gel. The gel is thoroughly washed with excess water for one dayand stored under water to avoid drying. The water content of this gel ismeasured as being 98.5% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.3 by adding hydrochloric acid (18%solution). To this solution, 0.10 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 isadded, and the solution is well mixed. After 6 hours the solution hasformed a gel and after 48 hours syneresis is observed. The gel isthoroughly washed with excess water for one day and stored under waterto avoid drying. The water content for this gel is measured as being95.5% (by volume).

(c) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18%solution). To this solution is added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water, and the solution is well mixed. After 3 hours at 50° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 98% (by volume).

(d) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18%solution). To this solution 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 isadded, and the solution is well mixed. After 3 hours at 50° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 95% (by volume).

(e) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18%solution). To this solution is added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water, and the solution is well mixed. After 40 minutes at 80° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 98% (by volume).

(f) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.8 by adding hydrochloric acid (18%solution). To this solution 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 isadded, and the solution is well mixed. After 40 minutes at 80° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 95% (by volume).

(g) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution is added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water, and the solution is well mixed. After 40 minutes at 80° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 98% (by volume).

(h) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 isadded, and the solution is well mixed. After 40 minutes at 80° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water avoid drying. The water contentfor this gel is estimated to be 95% (by volume).

EXAMPLE 27

Polymer gel containing chloramphenicol, prepared by radicalpolymerization of a water/DMSO (90:10) solution of the drug, acrylamideand methylene dimethacrylate

AIBN (0.010 g, 0.061 mmol) is added to a solution of acrylamide (5.00 g,70.34 mmol), methylene dimethacrylate prepared as described in Example4(a) (0.250 g, 1.36 mmol) and chloramphenicol (0.051 g, 0.157 mmol) inwater/DMSO(90:10, 20 ml) at 60° C. under a dry N₂ atmosphere, with goodstirring. AIBN (0.010 g, 0.061 mmol) is again added after 1.5 hours.After a total of 3 hours the reaction mixture is cooled to 20° C. Thereaction mixture then proves to be a soft gel. The gel does not dissolvein water, even after 7 days, whereas the corresponding acrylamidehomopolymer is water-soluble.

EXAMPLE 28

Polymer gel containing testosterone, prepared by radical polymerizationof a water/DMSO (90:10) solution of the drug, acrylamide and methylenediacrylate

AIBN (0.010 g, 0.061 mmol) is added to a solution of acrylamide (5.00 g,70.34 mmol), methylene diacrylate prepared as described in Example 4(b)(0.212 g, 1.36 mmol) and testosterone (0.050 g, 0.173 mmol) inwater/DMSO (90:10, 20 ml) at 60° C. under a dry N₂ atmosphere, with goodstirring. After 40 mins. the reaction mixture has turned into a gel. Thereaction mixture is kept at 60° C. for a total of 2 hours to completethe reaction. Upon cooling to 20° C. the testosterone crystallizes inthe gel. The gel does not dissolve in water, whereas the correspondingacrylamide homopolymer is water-soluble.

EXAMPLE 29

Polymer gel containing 5-fluorouracil, prepared by radicalpolymerization of a water/DMSO (14:1) solution of the drug, acrylamideand methylene diacrylate

An aqueous solution of 5-fluorouracil (5.00 ml, 250 mg/10 ml, 0.961mmol) is added to a solution of acrylamide (5.00 g, 70.34 mmol) andmethylene diacrylate prepared as described in Example 4(b) (0.212 g,1.36 mmol) in water/DMSO (90:10, 10 ml) at 60° C. under a dry N₂atmosphere, with good stirring. AIBN (0.010 g, 0.061 mmol) is then addedand after 35 mins. the reaction mixture has turned into a gel. Thereaction mixture is kept at 60° C. for a total of 2 hours to completethe reaction. The gel does not dissolve in water, whereas thecorresponding acrylamide homopolymer is water-soluble.

EXAMPLE 30

Polymer gel containing sulfadiazine, prepared by suspending the drug anaqueous solution of poly(vinyl alcohol) subsequently crosslinked withmethylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water and 0.20 g (0.8 mmol) of sulfadiazine, and the dispersion iswell mixed. After 40 minutes at 80° C. the solution has formed a gelwith the powder suspended in it. The gel is thoroughly washed withexcess water for one day and stored under water to avoid drying. Thewater content for this gel is estimated to be 98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.20g (0.8 mmol) of sulfadiazine, and the suspension is well mixed. After 40minutes at 80° C. the polymer has formed a gel with the powder suspendedin it. The gel is thoroughly washed with excess water for one day andstored under water to avoid drying. The water content for this gel isestimated to be 95% (by volume).

EXAMPLE 31

Polymer gel containing progesterone, prepared by suspending the drug inan aqueous solution of poly(vinyl alcohol) subsequently crosslinked withmethylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water and 0.07 g (0.2 mmol) of progesterone, and the dispersion iswell mixed. After 40 minutes at 80° C. the polymer has formed a gel withthe powder suspended in it. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.07g (0.2 mmol) of progesterone, and the suspension is well mixed. After 40minutes at 80° C. the polymer has formed a gel with the powder suspendedin it. The gel is thoroughly washed with excess water for one day andstored under water to avoid drying. The water content for this gel isestimated to be 95% (by volume).

EXAMPLE 32

Polymer gel containing 5-fluorouracil, prepared by dissolving the drugin an aqueous solution of poly(vinyl alcohol) subsequently crosslinkedwith methylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water and 13 mg (0.1 mmol) of 5-fluorouracil dissolved in 0.5 mlwater, and the solution is well mixed. After 40 minutes at 80° C. thesolution has formed a gel. The gel is thoroughly washed with excesswater for one day and stored under water to avoid drying. The watercontent for this gel is estimated to be 98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 13 mg(0.1 mmol) of 5-fluorouracil dissolved in 0.5 ml water, and the solutionis well mixed. After 40 minutes at 80° C. the solution has formed a gel.The gel is thoroughly washed with excess water for one day and storedunder water to avoid drying. The water content for this gel is estimatedto be 95% (by volume).

EXAMPLE 33

Polymer gel containing Omnipaque™, prepared by dissolving the diagnosticaid in an aqueous solution of poly(vinyl alcohol) subsequentlycrosslinked with methylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water and 1 ml of Omnipaque™ (300 mgI/ml), and the solution is wellmixed. After 40 minutes at 80° C. the solution has formed a gel. The gelis thoroughly washed with excess water for one day and stored underwater to avoid drying. The water content for this gel is estimated to be98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 0.1 g (0.35 mmol) of methylene di(3,3-dimethoxypropionate) prepared as described in Example 24 and 1 mlof Omnipaque™ (300 mgI/ml), and the solution is well mixed. After 40minutes at 80° C. the solution has formed a gel. The gel is thoroughlywashed with excess water for one day and stored under water to avoiddrying. The water content for this gel is estimated to be 95% (byvolume).

EXAMPLE 34

Polymer gel containing magnetic starch microspheres, prepared bysuspending the material in an aqueous solution of poly(vinyl alcohol)subsequently crosslinked with methylene di(3,3-dimethoxypropionate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 19.6 mg (0.07 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 in 1 mlof water and 0.5 ml of a suspension containing magnetic starchmicrospheres prepared as described in WO 85/02772 (Schroder) (7.5 mgFe/ml, 0.9% NaCl, 0.5% glycerol), and the suspension is well mixed.After 40 minutes at 80° C. the polymer has formed a gel with themagnetic material suspended in it. The gel is thoroughly washed withexcess water for one day and stored under water to avoid drying. Thewater content for this gel is estimated to be 98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution are added 0.1 g (0.35 mmol) of methylenedi(3,3-dimethoxypropionate) prepared as described in Example 24 and 0.5ml of a suspension containing magnetic starch microspheres prepared asdescribed in WO 85/02772 (Schroder) (7.5 mg Fe/ml, 0.9% NaCl, 0.5%glycerol), and the suspension is well mixed. After 40 minutes at 80° C.the polymer has formed a gel with the magnetic material suspended in it.The gel is thoroughly washed with excess water for one day and storedunder water to avoid drying. The water content for this gel is estimatedto be 97% (by volume).

EXAMPLE 35

Homopolymerisation of methylene dimethacrylate

0.5 g (2.7 mmol) of methylene dimethacrylate prepared as described inExample 4(a) is blended with 2.5 mg (15 μmol) of AIBN. After 2 hours at70° C. the monomer has formed a hard solid. This polymer is insoluble,indicating that its structure is a tightly crosslinked network.

EXAMPLE 36

Homopolymerisation of (2-methacryloyloxy)ethyl methacryloyloxymethylcarbonate

0.4340 g (1.6 mmol) of (2-methacryloyloxy)ethyl methacryloyloxymethylcarbonate prepared as described in Example 4(d) is blended with 22.0 mg(13.2 μmol) of AIBN. After 2 hours at 70° C. the monomer has formed ahard solid. This polymer is insoluble, indicating that its structure isa tightly crosslinked network.

EXAMPLE 37

Emulsion copolymerisation of methylene dimethacrylate and methylmethacrylate

50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water ispre-heated to 60° C. under a nitrogen atmosphere. 0.20 g (1.09 mmol) ofmethylene dimethacrylate prepared as described in Example 4(a) and 9.80g (0.098 mol) of methyl methacrylate monomer are added under vigorousstirring. The polymerisation is initiated with ametabisulphite/persulphate redox system comprising 1.6 mg (7.2 μmol)potassium metabisulphite and 0.08 mg (0.3 μmol) potassium persulphate.The polymerisation is permitted to proceed for 8 hours before cooling toroom temperature. The resultant emulsion has a solids content of 11.1%which corresponds to a degree of conversion of 66%. The recoveredpolymer is not soluble in THF, a good solvent for poly(methylmethacrylate), indicating that the polymer is crosslinked.

EXAMPLE 38

Emulsion copolymerisation of methylene dimethacrylate and styrene

50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water ispre-heated to 60° C. under a nitrogen atmosphere. 0.20 g (1.09 mmol) ofmethylene dimethacrylate prepared as described in Example 4(a) and 9.80g (0.094 mol) styrene monomer are added under vigorous stirring. Thepolymerisation is initiated with a metabisulphite/persulphate redoxsystem comprising 1.6 mg (7.2 μmol) potassium metabisulphite and 0.08 mg(0.3 μmol) potassium persulphate. The polymerisation is permitted toproceed for 8 hours before cooling to room temperature. The resultantemulsion has a solids content of 11.2% which corresponds to a degree ofconversion of 68%. The recovered polymer is not soluble in THF, a goodsolvent for polystyrene, indicating that the polymer is crosslinked.

EXAMPLE 39

Emulsion copolymerisation of acryloyloxymethyl 4-acryloyloxybutylcarbonate and methyl methacrylate

50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water ispre-heated to 60° C. under a nitrogen atmosphere. 0.20 g (0.74 mmol) ofacryloyloxymethyl 4-acryloyloxybutyl carbonate prepared as described inExample 4(k) and 9.80 g (0.098 mol) of methyl methacrylate monomer areadded under vigorous stirring. The polymerisation is initiated with ametabisulphite/persulphate redox system comprising 1.6 mg (7.2 μmol)potassium metabisulphite and 0.08 mg (0.3 μmol) potassium persulphate.The polymerisation is permitted to proceed for 8 hours before cooling toroom temperature. The resultant emulsion has a solids content of 11.2%which corresponds to a degree of conversion of 67%. The recoveredpolymer is not soluble in THF, a good solvent for poly(methylmethacrylate), indicating that the polymer is crosslinked.

EXAMPLE 40

Emulsion copolymerisation of acryloyloxymethyl 4-acryloyloxybutylcarbonate and styrene

50 ml of a 1% wt/vol solution of sodium dodecyl sulphate in water ispre-heated to 60° C. under a nitrogen atmosphere. 0.20 g (0.74 mmol) ofacryloyloxymethyl 4-acryloyloxybutyl carbonate prepared as described inExample 4(k) and 9.80 g (0.094 mol) of styrene monomer are added undervigorous stirring. The polymerisation is initiated with ametabisulphite/persulphate redox system comprising 1.6 mg (7.2 μmol)potassium metabisulphite and 0.08 mg (0.3 μmol) potassium persulphate.The polymerisation is permitted to proceed for 8 hours before cooling toroom temperature. The resultant emulsion has a solids content of 12%which corresponds to a degree of conversion of 72%. The recoveredpolymer is not soluble in THF, a good solvent for polystyrene,indicating that the polymer is crosslinked.

EXAMPLE 41

Polymer gel containing magnetic starch microspheres prepared by radicalpolymerization of a water/DMSO (90:10) suspension of magnetic starchmicrospheres acrylamide and 1-acryloyloxyethyl 4-acryloyloxybutylcarbonate

An aqueous suspension of magnetic starch microspheres prepared asdescribed in WO 85/02722 (Schroder) (0.50 ml from a solution containing7.5 mg Fe/ml, 0.9% NaCl and 0.5% glycerol) is added to a solution ofacrylamide (5.00 g, 70.34 mmol) and 1-acryloyloxyethyl4-acryloyloxybutyl carbonate prepared as described in Example 4(l)(0.359 g, 1.36 mmol) in water/DMSO (90:10, 10 ml) at 60° C. under a dryN₂ atmosphere, with good stirring. AIBN, (0.010 g, 0.061 mmol) is thenadded and after approximately 40 minutes the reaction mixture has turnedinto a gel. The reaction mixture is kept at 60° C. for a total of 2hours to complete the reaction. The gel does not dissolve in water,whereas the corresponding acrylamide homopolymer is water-soluble.

EXAMPLE 42

Polymer from hexamethylene di(chloromethyl carbonate) and2,3,5,6-tetraiodoterephthalic acid

A solution of hexamethylene di(chloromethyl carbonate) prepared asdescribed in Example 19 (0.61 g, 2 mmol) in dry DMF (2 ml) is addeddropwise to a suspension of di-potassium 2,3,5,6-tetraiodoterephthalate(1.49 g, 2 mmol) and 18-crown-6 (0.03, 0.1 mmol) in drydimethylformamide (18 ml) under an N₂ atmosphere. After 4 days at 60° C.the solvent is removed under reduced pressure (0.5 mm Hg). The residueis dissolved in chloroform (400 ml) and washed with saturated aqueoussodium hydrogen carbonate (3×200 ml) and water (2×200 ml). The organicphase is dried (MgSO₄) and evaporated to give 1.16 g of product. ¹ H NMR(300 MHz): δ 1.38-1.45 (m, area=0.24), 1.65-1.76 (m, area=0.24),4.18-4.25 (m, area=0.23), 5.73 (s, area=0.01), 5.99 (s, area=0.21). Thearea ratio between the signal at δ 5.73 from the α-chloromethylene groupof the aliphatic monomer and the signal at δ 5.99 from the methylenediester groups confirms that a polymer is formed.

EXAMPLE 43

Covalent attachment of MCPA to 2-hydroxyethyl methacrylate polymercrosslinked with 0.5% 2-methacryloyloxyethyl methacryloyloxyethylcarbonate

The gel described in Example 10 (2.0 g) is swelled in 20 ml dry DMSO.The gel suspension is added a solution of 2-methyl-4-chloro-phenoxyacetic acid (MCPA) (2.0 g, 10 mmol), N-ethyl-N'-(3-(N"-dimethylamino)propyl) carbodiimide and 4-pyrrolidinopyridine (160 mg, 1 mmol) in 30 mldry DMSO, under a dry nitrogen atmosphere. The suspension is shaken for24 hours at room temperature, and the gel is washed with DMSO andfinally water and dried in vacuo to yield the product. The resultingwater suspensible gel contains the highly water soluble weed killer MCPAcovalently attached to the gel and provides sustained release of theagrochemical.

EXAMPLE 44

Covalent attachment of5-acetylamino-3-(N-methylacetylamino)-2,4,6-triiodobenzoic acid(Isopaque) to 2-hydroxyethyl methacrylate polymer crosslinked with 0.5%2-methacryloyloxyethyl methacryloyloxymethyl carbonate

(a) The Isopaque amide of β-alanine-O-benzyl ester

Potassium carbonate (0.69, 5 mmol) is added to a solution ofH-β-alanine-O-benzyl ester (1.76 g, 5 mmol) in dry dimethylformamide (50ml) at 0° C. After 10 minutes at ambient temperature,5-acetylamino-3-(N-methylacetylamino)-2,4,6-triiodobenzoyl chloride(Isopaque acid chloride) (3.23 g, 5 mmol) dissolved in drydimethylformamide (20 ml) is added dropwise to the suspension at 0° C.under a nitrogen atmosphere. The reaction mixture is heated to 50° C.After 24 hours the solvent is removed under reduced pressure andchloroform (500 ml) and water (200 ml) are added. The organic phase iswashed with saturated aqueous sodium hydrogen carbonate (100 ml), 0.01MHCl (100 ml) and water (2×100 ml). After drying of the organic phaseevaporation of the solvent gives 3.10 g product (79%). ¹ H NMR (300MHz): δ 1.72-1.83 (m), 2.15-2.23 (m), 2.72-2.81 (m), 3.0-3.09 (m),3.67-3.78 (m), 5.05-5.20 (m), 6.6-7.0 (m), 7.31-7.35 (m), 8.5-8.9 (m).

(b) Debenzylation of the Isopaque amide of β-alanine-O-benzyl ester

The Isopaque amide of β-alanine-O-benzyl ester prepared in (a) above(1.578 g, 2 mmol) is dissolved in dry methanol (50 ml). Palladium oncharcoal (10%, 0.4 g) is added in one portion with stirring of thereaction mixture. Hydrogen gas is bubbled into the solution for twohours, and then the reaction mixture is stirred for a further 2 hours.Filtration and evaporation of the solvent yield a yellow residue, whichis purified on a weakly cationic ion exchanger to yield the product.

(c) Attachment of5-acetylamino-3-(N-methylacetylamino)-2,4,6-triiodobenzoic acid(Isopaque) to polymer gel

The carboxylic acid from (b) above is attached to the gel described inExample 10 using the method described in Example 43.

EXAMPLE 45

Methylene di(3-methoxypropenoate)

Methylene di(3,3-dimethoxypropionate) prepared as described in Example24 (14.01 g, 50 mmol) and a catalytic amount of p-toluene sulfonic acidis added to toluene (250 ml). The methanol is removed by warming thereaction under an N₂ atmosphere. When the reaction is complete thetoluene is distilled off under reduced pressure. Diethyl ether (250 ml)is added and the mixture is washed with saturated aqueous sodiumhydrogen carbonate (5×50 ml) and water (3×50 ml). The organic layer isdried (MgSO₄) before evaporation to give 8.52 g (79%) product.

EXAMPLE 46

Aqueous polymer gel prepared by crosslinking an aqueous solution ofpoly(vinyl alcohol) with methylene di(3-methoxypropenoate)

(a) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%solution). To this solution is added 55 mg (0.23 mmol) of methylenedi(3-methoxypropenoate) prepared as described in Example 45 in 1 ml of50:50 dioxane/water, and the solution is well mixed. After 40 minutes at80° C. the solution has formed a gel. The gel is thoroughly washed withexcess water for one day and stored under water to avoid drying. Thewater content for this gel is estimated to be 98% (by volume).

(b) 5 g of an aqueous solution of poly(vinyl alcohol) (6.25 w % inwater, 7.0 mmol with respect to monomer units, average M.W. 126 000, 98%hydrolyzed) is adjusted to pH=0.4 by adding hydrochloric acid (18%)solution. To this solution is added 110 mg (0.56 mmol) of methylenedi(3-methoxypropenoate) prepared as described in Example 45 in 2 ml of50:50 dioxane/water, and the solution is well mixed. After 40 minutes at80° C. the solution has formed a gel. The gel is thoroughly washed withexcess water for one day and stored under water to avoid drying. Thewater content for this gel is estimated to be 97% (by volume).

EXAMPLE 47

(a) Methylene bis(10-undecenoate)

10-Undecylenic acid (12.75 g, 75 mmol) is dissolved in 100 ml water.Cesium carbonate (13.04 g, 40 mmol) is added to the mixture. The wateris removed under reduced pressure and the salt dried for 2 hours invacuo. The cesium salt is mixed with 150 ml DMF and diiodomethane isadded to the solution. The reaction is stirred for 3 days at 60° C.under an N₂ atmosphere. DMF is then removed under reduced pressure. Theresidue is purified through silica gel with hexane/ethyl acetate (8:2)as eluant. The solvent is evaporated to give 7.18 g (54%) product. ¹ HNMR (300 MHz, CDCl₃): δ 1.2-1.4 (10×CH₂, m), 1.6 (2×CH₂, m), 2.0 (2×CH₂,m), 2.19 (2×CH₂, t), 4.9 (2×H₂ C═, m), 5.88 (O--CH₂ --O, s), 5.9 (2×HC═,m). ¹³ C NMR (300 MHz, CDCl₃): δ 24.92-33.98 (8×CH₂), 79.04 (O--CH₂--O), 114.18 (═CH₂), 139.11 (═CH), 172.48 (C═O).

(b) Methylene bis(10,11-epoxyundecanoate)

Methylene bis(10-undecenoate) (8.8 g, 25 mmol) is added under an N₂atmosphere to methylene chloride and cooled to 0° C.Metachloroperbenzoic acid 55% (15.75 g, 50 mmol) is added to methylenechloride (150 ml) and the organic layer is separated and dried (MgSO₄).The metachloroperbenzoic acid is then added dropwise to the diester.After completed addition the temperature is increased to 25° C. After 5hours the reaction is complete. The mixture is washed with saturatedaqueous sodium sulphite (75 ml) and saturated aqueous sodium hydrogencarbonate (2×75 ml). The organic layer is purified on neutral aluminiumoxide. The solvent is removed under reduced pressure to yield 8.45 g(82%) product. ¹ HNMR (300 MHz, CDCl₃): δ 1.2-1.7(14×CH₂, m), 2.35(2×CH₂CO,t), 2.45 (2×CH,q), 2.75 (2×CH,q), 2.90 (2×CH,m), 5.75 (O--CH₂ --O).¹³ C NMR (300 MHz, CDCl₃): δ 24.58 (CH₂), 25.99 (CH₂), 28.94 (CH₂),29.09 (CH₂), 29.32 (2×CH₂), 32.45 (CH₂), 33.92 (CH₂), 47.06 (CH₂ --O),52.36 (CH--O), 79.06 (O--CH₂ --O), 172.2 (C═O).

EXAMPLE 48

(a) Methylene dibenzyloxyacetate

Benzyloxyacetic acid (49.8 g, 300 mmol) is dissolved in a 500 ml mixtureof water and MeOH (60:40), and cesium carbonate (48.9 g, 150 mmol) isadded to the solution. The solvent is evaporated under reduced pressureand residual water is removed azeotropically with benzene. The salt isdissolved in 1500 ml DMF and diiodomethane (40.2 g, 150 mmol) is addedto the solution. The reaction mixture is stirred for 3 days at 60° C.under an N₂ atmosphere. The DMF is removed under reduced pressure andthe residue is dissolved in ether (250 ml) and washed with saturatedaqueous sodium hydrogen carbonate (250 ml) and water (3×75 ml) beforedrying (MgSO₄). The solvent is evaporated and the residue is purifiedthrough silica gel with hexane/ethyl acetate (7:3) as eluant to give23.6 g (46%) product. ¹ H NMR (300 MHz, CDCl₃): δ 4.1 (2×CH₂, s), 4.6(2×CH₂, s), 5.9 (O--CH₂ --O, s), 7.35 (2×C₆ H₅, m).

(b) Methylene dihydroxyacetate

Methylene dibenzyloxyacetate (0.52 g, 1.5 mmol) and Pd/C (100 mg, 10%)are added to dry ethanol (100 ml). Hydrogen (1 atm) is introduced andthe reaction is complete after 16 hours at room temperature, whereuponthe reaction mixture is filtered and the solvent is evaporated underreduced pressure (0.01 mmHg) to yield 0.23 g (95%) product. ¹ H NMR (200MHz, MeOH): δ 4.2 (CH₂, s), 4.9 (OH), 5.9 (OCH₂ O, s). The product maybe used to form polyesters with di- or poly-acids and to formpolyurethanes with isocyanates.

EXAMPLE 49

Homopolymerisation of methylene diepoxypropionate

Anhydrous tert.butylhydroperoxide (3.3 ml, 3M) and BuLi (6.7 ml, 1.5M)are dissolved in 30 ml cold (-78° C.) THF. The solution is stirred for 5minutes before adding methylene diacrylate (0.78 g, 5 mmol). Thereaction is performed under N₂ atmosphere for 1 hour. The cold mixtureis filtered through neutral aluminium oxide and evaporated to yield atransparent polymer. The solubility properties of the product indicatethat it is a polymer.

EXAMPLE 50

Homopolymerisation of 1-acryloyloxyethyl 4-acryoyloxybutyl carbonate

348.2 mg (1.22 mmol) of 1-acryloyloxyethyl 4-acryoyloxybutyl carbonateprepared as described in Example 4(l) is blended with 1.7 mg (10.2 μmol)AIBN. After 2 hours at 70° C. the monomer has formed a hard solid. Thispolymer is insoluble, indicating that its structure is a tightlycrosslinked network.

EXAMPLE 51

Epoxy resin based on methylene bis(10,11-epoxyundecanoate) and analiphatic polyamine

A sample of methylene bis(10,11-epoxyundecanoate) prepared as describedin Example 47 is blended with an equal weight of a commercial aliphaticpolyamine curing agent. This mixture is cured on the surface of a glassplate at 70° C. The resin is observed to have hardened and good bondingis obtained within 2 hours of mixing.

EXAMPLE 52

Polymer from 1,6-diisocyanatohexane and methylene di(p-hydroxybenzoate)

1,6-Diisocyanatohexane (0.927 g, 5.51 mmol) is added to a solution ofmethylene di(p-hydroxybenzoate) prepared as described in Example 4(o)(1.588 g, 5.51 mmol) in DMF (15 ml) under a dry N₂ atmosphere. Thereaction mixture is heated to 100° C. for 3 days before the solvent isremoved under reduced pressure at 50° C. Upon cooling to 20° C. theproduct turns into a rubber-like material which is practically insolublein a 1:1 mixture of chloroform and DMSO, indicating formation of apolymer.

EXAMPLE 53

Characterisation of the size of the polymers made in Examples 37, 38, 39and 40

The characterisations are performed on a Malvern PS/MW 4700 usingBuccard cells. Each sample is diluted until an opaque solution forms andis attemperated to 25° C. prior to analysis. Viscosity of water=0.891 cPis used, and instrument settings are: Light Power=70 mW, PM-aperture=200m, Scattering angle=90°, Mode=Manual, Serial Configuration, Sampletime=4 s, Experimental duration=90 s, Calculus mode=model independent,fit error minimized. To obtain results for the mass distribution a"Particle Refractive Index"=1.45 is used. Each sample is analysed intriplicate.

Mass mean particle hydrodynamic diameter (Dh) and distribution standarddeviation (SD-distribution) for each sample are shown on the followingTable. Experimental SD is shown in brackets.

    ______________________________________                                        Example     Dh          SD-distribution                                       ______________________________________                                        37          57.5 (±1.5) nm                                                                         11.2 (±1.7) nm                                     38          58.7 (±0.9) nm                                                                         12.1 (±1.3) nm                                     39          56.7 (±0.7) nm                                                                         16.6 (±1.2) nm                                     40          62.1 (±1.6) nm                                                                         14.0 (±2.6) nm                                     ______________________________________                                    

EXAMPLE 54

(a) Enzyme-catalyzed hydrolysis of acrylamide polymer crosslinked with2% acryloyloxymethyl 4-acryloyloxybutyl carbonate

432 mg samples of the polymer described in Example 12 and 50 ml 0.9%NaCl (Sterile, Hydro Pharma) are added to each of two reaction vials. Toone of the vials is also added 1000 μl esterase (Sigma, E-2138, 2530 U).The pH within each vial is kept constant at 8.4 by adding 0.10M NaOH. Byrecording the consumption of NaOH the rates of hydrolysis arecalculated. During 21 hours, hydrolysis of the polymer with esterase isfound to be 8.5 times faster than the control without esterase.

(b) Enzyme-catalyzed hydrolysis of acrylamide polymer crosslinked with2% methylene dimethacrylate compared with control polyester

To one vial are added 500 mg acrylamide polymer crosslinked with 2%methylene dimethacrylate prepared according to the method of Example5(a), 40 ml (0.16M, pH 7.4) PBS (phosphate buffer) and 800 μl esterase(Sigma, E-2138, 2024 U).

As a control 500 mg acrylamide polymer crosslinked with 2% ethylenedimethacrylate (prepared according to the method of Example 5(a) butusing ethylene dimethacrylate instead of methylene dimethacrylate), 40ml (0.16M, pH 7.4) PBS (phosphate buffer) and 800 μl esterase (Sigma,E-2138, 2024 U) are added to a second vial.

For the control polyester, pH of the buffer decreases from 7.1 to 6.9during 200 hours, while pH in the buffer solution containing acrylamidepolymer crosslinked with methylene dimethacrylate decreases from 7.1 to6.4 during 24 hours, indicating that the acid metabolites are formedmuch faster for methylene dimethacrylate polymer than for the controlpolyester.

EXAMPLE 55

Polymer from starch crosslinked with methylenebis(10,11-epoxyundecanoate)

Titanum (IV) isopropoxide (1.11 g, 3.9 mmol) is added to a solution ofmethylene bis(10,11-epoxyundecanoate) prepared as described in Example47 (1.0 g, 2.6 mmol) and starch (1.0 g) in dry DMSO (50 ml). Thereaction mixture is stirred for 4 hours at ambient temperature.Chloroform/ether (250 ml, 1:1) is added, the oily material is dissolvedin water and extracted with chloroform (2×50 ml). The aqueous phase issubjected to dialysis or gel filtration to furnish the polymer.

EXAMPLE 56

Polymer from dextran 70000 crosslinked with methylene bis(10,11-epoxyundecanoate)

Titanum (IV) isoproxide (1.11 g, 3.9 mmol) is added to a solution ofmethylene bis(10,11-epoxyundecanoate) prepared as described in Example47 (1.0 g, 2.6 mmol) and dextran 70,000 in dry DMSO (50 ml). Thereaction mixture is stirred for 4 hours at ambient temperature.Chloroform/ether (250 ml, 1:1) is added, the oily material is dissolvedin water and extracted with chloroform (2×50 ml). The aqueous phase issubjected to dialysis or gel filtration to furnish the polymer.

EXAMPLE 57

Polymer from protein crosslinked with methylenebis(10,11-epoxyundecanoate)

Methylene bis(10,11-epoxyundecanoate) prepared as described in Example47 (1.0 g, 2.6 mmol) is added to a solution of human serum albumin (1.0g) in buffer (50 ml). The reaction mixture is stirred at ambienttemperature overnight and evaporated. The polymer is washed severaltimes with tetrahydrofuran and dried under reduced pressure.

We claim:
 1. Biodegradable polymers comprising diester units of theformula (I)

    --CO--O--C(R.sup.1 R.sup.2)--O--CO--                       (I)

where R¹ and R² each represents a hydrogen atom or a carbon-attachedmonovalent organic group or R¹ and R² together form a carbon-attacheddivalent organic group.
 2. Biodegradable polymers as claimed in claim 1in which the diester units have the formula (II)

    --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m ](II)

where m and n, which may be the same or different, are 0 or
 1. 3.Biodegradable polymers as claimed in claim 2 in which the diester unitshave the formula (III)

    --(O).sub.n --CO--O--C(R.sup.1 R.sup.2)--O--CO--(O).sub.m --R.sup.3 ](III)

where R³ is a carbon-attached divalent organic grouping. 4.Biodegradable polymers as claimed in claim 2 wherein n is 0 and m is 0or
 1. 5. Biodegradable polymers as claimed in claim 1 in which R¹ and R²are each hydrogen or a carbon-attached hydrocarbyl or heterocyclicgroup.
 6. Biodegradable polymers as claimed in claim 5 in which R¹ andR² are each hydrogen or an aliphatic group having up to 10 carbon atoms,a cycloalkyl group having up to 10 carbon atoms, an araliphatic grouphaving up to 20 carbon atoms, an aryl group having up to 20 carbon atomsor a heterocyclic group having up to 20 carbon atoms and one or moreheteroatoms selected from the group consisting of O, S and N. 7.Biodegradable polymers as claimed in claim 1 which are block or graftcopolymers.
 8. Biodegradable polymers as claimed in claim 1 in the formof surgical implants, soft tissue prostheses, sponges, films, wounddressings, flexible sheets, containers and delayed release formulationsfor drugs and agricultural chemicals, particulate imaging agents orplasticisers.
 9. Biodegradable polymers as claimed in claim 1 comprisinga plurality of polymer chains cross-linked by diester units of formula(I).
 10. Biodegradable polymers as claimed in claim 3 wherein n is 0 andm is 0 or
 1. 11. Biodegradable polymers as claimed in claim 3 wherein R¹and R² are each hydrogen or a carbon-attached hydrocarbyl orheterocyclic group.
 12. Biodegradable polymers as claimed in claim 3 inwhich R³ is selected from the group consisting of alkylene andalkenylene groups having up to 20 carbon atoms, cycloalkylene groupshaving up to 10 carbon atoms, aralkylene groups having up to 20 carbonatoms, arylene groups having up to 20 carbon atoms, heterocyclic groupshaving up to 20 carbon atoms and one or more heteroatoms selected fromthe group consisting of O, S and N, and any of the preceding groupsinterrupted by oxygen, substituted by oxygen or interrupted andsubstituted by oxygen.
 13. Biodegradable polymers as claimed in claim 1which are linear polymers.